CN101663317A

CN101663317A - glucagon-like protein-1 receptor (glp-1r) agonist compounds

Info

Publication number: CN101663317A
Application number: CN200880007364A
Authority: CN
Inventors: 柯特·布拉德肖; 萨库马·萨卡穆里; 傅彦文; 布赖恩·奥茨; 乔尔·德沙奈斯; 戴维·图梅尔蒂
Original assignee: Covx Technologies Ireland Ltd
Current assignee: Covx Technologies Ireland Ltd
Priority date: 2007-01-05
Filing date: 2008-01-07
Publication date: 2010-03-03

Abstract

The present invention provides glucagon-like protein 1 receptor targeting compounds which, comprise glucagon-like protein 1 receptor targeting agent-linker conjugates linked to a combining site of anantibody. Various uses of the compounds are provided, including methods to prevent or treat diabetes or diabetes-related conditions.

Description

Glucagon albumen-1 acceptor GLP-1R agonist compound

Related application

The application requires in the U.S. Provisional Application the 60/879th of submission on January 5th, 2007, No. 048, the U.S. Provisional Application the 60/939th submitted on May 23rd, 2007, No. 831 and the U.S. Provisional Application the 60/945th submitted on June 20th, 2007, No. 319 right of priority is introduced its disclosed full content by reference herein.

Technical field

The present invention relates to promote the novel cpd of insulin secretion and lower glucose level, and the method for making and use these compounds.Particularly, the present invention relates in conjunction with and activate the compound of glucagon albumen 1 acceptor (GLP-1R).

Background technology

Type ii diabetes is most popular diabetes type.This disease is caused by insulin resistant and pancreatic beta cell depletion, and this insulin secretion that has caused glucose to stimulate reduces.The insulin secretion and the glucagon suppression excretory compound incretin (incretin) that stimulate glucose to rely on occur as the attractive material standed for for the treatment of type ii diabetes.Have been found that to be glucose pancreotropic hormone polypeptide (GIP) and glucagon-like peptide (7-36) acid amides (GLP-1) at two kinds of incretin of the external β of improvement cell function.As if GIP is not attractive treatment material standed for, because diabetes β cell is relatively resisted its effect.Yet diabetes β cell is to the effect sensitivity of GLP-1.

Except increasing insulin secretion and minimizing glucagon secretion, the amino acid whose GLP-1 peptide of 30-also stimulates the proinsulin genetic transcription, slows down the gastric emptying time and reduces ingestion of food.GLP-1 by with glucagon-like peptide 1 acceptor (GLP-1R, a kind of infer possible 7-transmembrane domain receptors) in conjunction with bringing into play its physiologic effect.

The shortcoming that the treatment of GLP-1 is used is the transformation period (1 minute～2 minutes) in its short body.This short transformation period is the result that this peptide is subjected to the quick degraded of dipeptidyl peptidase 4 (DPP-IV).This causes the transformation period that shows prolongation and keeps stimulating the evaluation or the exploitation of the GLP-1 analogue of the active ability of GLP-1R simultaneously.The example of these analogues comprises incretin analogue-4 (exendin-4) and GLP-1-Gly8.

Although developed the GLP-1 analogue that several maintenance insulinotropic activities show the transformation period of prolongation simultaneously, but still need have the GLP-1R agonist of the pharmacokinetics feature of improvement.

Not that also should not to be taken as be any type of approval or the suggestion that the technology of institute's reference is constituted the part of ubiquity general knowledge to the reference of any technology in this specification sheets.

Summary of the invention

Herein disclosed is by with the covalently bound composition that forms of the binding site of one or more GLP-1R agonist peptides and one or more antibody, and make and use these method for compositions.GLP-1R agonist (GA) compound of transformation period in the body that has improvement is provided in some embodiments.The GA target compound by with the agent of GA target directly or through getting involved joint and antibody combining site is covalently bound forms.The pharmaceutical composition that comprises target compound of the present invention and pharmaceutically acceptable carrier also is provided.

In some embodiments, provide GLP-1R agonist (GA) peptide.In some aspects, the invention provides the agent of GA target, the agent of wherein said GA target is the peptide agonists of GLP-1 acceptor, and the agent of described GA target comprises the peptide that comprises with the basic homologous sequence of following sequence:

R ¹-H ¹x ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹x ¹⁰S ¹¹x ¹²x ¹³x ¹⁴E ¹⁵x ¹⁶x ¹⁷A ¹⁸x ¹⁹x ²⁰x ²¹F ²²x ²³x ²⁴x ²⁵x ²⁶x ²⁷x ²⁸x ²⁹x ³⁰x ³¹x ³²x ³³x ³⁴x ³⁵x ³⁶x ³⁷x ³⁸x ³⁹-R ²，

Wherein:

R ¹Disappearance or CH ₃, C (O) CH ₃, C (O) CH ₂CH ₃, C (O) CH ₂CH ₂CH ₃Or C (O) CH (CH ₃) CH ₃

R ²Disappearance or OH, NH ₂, NH (CH ₃), NHCH ₂CH ₃, NHCH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₃, NHCH ₂CH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₂CH ₃, NHC ₆H ₅, NHCH ₂CH ₂OCH ₃, NHOCH ₃, NHOCH ₂CH ₃, carboxyl-protecting group, lipid is fatty acid-based or sugared, and

x ²Be that (wherein term " blocking group " is at x such as blocking groups such as Aib, A, S, T, V, L, I or D-Ala ²Context in be meant residue or the group that can block such as some cleavage reaction of DPP-4 cutting), x ¹⁰Be V, L, I or A, x ¹²Be S or K, x ¹³Be Q or Y, x ¹⁴Be G, C, F, Y, W, M or L, x ¹⁶Be K, D, E or G, x ¹⁷Be E or Q, x ¹⁹Be L, I, V or A, x ²⁰Be Orn, K (SH), R or K, x ²¹Be L or E, x ²³Be I or L, x ²⁴Be A or E, x ²⁵Be W or F, x ²⁶Be L or I, x ²⁷Be I, K or V, x ²⁸Be R, Orn, N or K, x ²⁹Be Aib or G, x ³⁰Be any amino acid and be preferably G or R, x ³¹Be P or disappearance, x ³²Be S or disappearance, x ³³Be S or disappearance, x ³⁴Be G or disappearance, x ³⁵Be A or disappearance, x ³⁶Be P or disappearance, x ³⁷Be P or disappearance, x ³⁸Be P or disappearance, x ³⁹Be S or disappearance, x ⁴⁰Be to connect residue or disappearance, in addition, x wherein ¹⁰, x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁷, x ¹⁹, x ²⁰, x ²¹, x ²⁴, x ²⁶, x ²⁷, x ²⁸, x ³², x ³³, x ³⁴, x ³⁵, x ³⁶, x ³⁷, x ³⁸, x ³⁹Or x ⁴⁰One of replace by connecting residue ([LR]-), described connection residue comprise can with antibody combining site through the covalently bound nucleophilic side chain of intermediate head, and wherein said connection residue is K (SH).In these embodiments, x ²Can be Aib.

Compound of the present invention can comprise peptide, and described peptide comprises and the basic homologous sequence of one or more compounds that is selected from following compounds:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)，

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAibEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)，

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAibEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAibEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK(SH)-R ²(SEQ?ID?NO：114)，

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)，

R ¹-HAibEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)，

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：171)，

R ¹-HAibEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：116)，

R ¹-HAibEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：117)，

R ¹-HAibEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：118)，

R ¹-HAibEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：119)，

R ¹-HAibEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAibR-R ²(SEQ?ID?NO：120)，

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAibR-R ²(SEQ?ID?NO：121)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIK(SH)WLIKAibR-R ²(SEQ?ID?NO：122)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWK (SH) IKAibR-R ²(SEQ ID NO:123) and

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：124)。

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)，

R ¹-HAibEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)，

R ¹-HAibEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：116)，

R ¹-HAibEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：117)，

R ¹-HAibEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAibR-R ²(SEQ?IDNO：118)，

R ¹-HAibEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：119)，

R ¹-HAibEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAibR-R ²(SEQ?ID?NO：120)，

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAibR-R ²(SEQ?ID?NO：121)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIK (SH) WLIKAibR-R ²(SEQ ID NO:122) and

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWK(SH)IKAibR-R ²(SEQ?ID?NO：123)。

R ^1-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)，

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAibEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)，

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAibEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAibEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK (SH)-R ²(SEQ ID NO:114) and

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)。

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)，

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAibEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)，

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAibEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAibEGTFTSDLK (SH) KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ ID NO:113) and

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)。

Compound of the present invention can comprise peptide, and described peptide comprises the sequence that is selected from following sequence:

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAibEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAibEGTFTSDLK (SH) KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ ID NO:113) and

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)。

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAibEGTFTSDLSKQK (SH) EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ ID NO:111) and

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)。

In some aspects, the invention provides the agent of GA target, the agent of wherein said GA target is the peptide agonists of GLP-1 acceptor, and the agent of described GA target comprises the peptide that comprises with the basic homologous sequence of following sequence:

R ¹-H ¹x ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹x ¹⁰S ¹¹x ¹²x ¹³x ¹⁴E ¹⁵x ¹⁶x ¹⁷A ¹⁸x ¹⁹x ²⁰x ²¹F ²²x ²³x ²⁴x ²⁵x ²⁶x ²⁷x ²⁸x ²⁹x ³⁰x ³¹x ³²x ³³x ³⁴x ³⁵x ³⁶x ³⁷x ³⁸x ³⁹-R ²

Wherein

R ¹Disappearance or CH ₃, C (O) CH ₃, C (O) CH ₂CH ₃, C (O) CH ₂CH ₂CH ₃Or C (O) CH (CH ₃) CH ₃With

R ²Disappearance or OH, NH ₂, NH (CH ₃), NHCH ₂CH ₃, NHCH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₃, NHCH ₂CH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₂CH ₃, NHC ₆H ₅, NHCH ₂CH ₂OCH ₃, NHOCH ₃, NHOCH ₂CH ₃, carboxyl-protecting group, lipid is fatty acid-based or sugared,

x ²Be such as blocking groups such as Aib, A, S, T, V, L, I or D-Ala, x ¹⁰Be V, L, I or A, x ¹²Be S or K, x ¹³Be Q or Y, x ¹⁴Be G, C, F, Y, W, M or L, x ¹⁶Be K, D, E or G, x ¹⁷Be E or Q, x ¹⁹Be L, I, V or A, x ²⁰Be Orn, K (SH), R or K, x ²¹Be L or E, x ²³Be I or L, x ²⁴Be A or E, x ²⁵Be W or F, x ²⁶Be L or I, x ²⁷Be I, K or V, x ²⁸Be R, Orn, N or K, x ²⁹Be Aib or G, x ³⁰Be any amino acid and be preferably G or R, x ³¹Be P or disappearance, x ³²Be S or disappearance, x ³³Be S or disappearance, x ³⁴Be G or disappearance, x ³⁵Be A or disappearance, x ³⁶Be P or disappearance, x ³⁷Be P or disappearance, x ³⁸Be P or disappearance, x ³⁹Be S or disappearance, x ⁴⁰Be to connect residue or disappearance,

And wherein said peptide is covalently bound through intermediate head (L ') and antibody combining site, and L ' and C end or to be connected the nucleophilic side chain of residue ([LR]-) covalently bound, thereby-[LR]-be selected from K, R, Y, C, T, S, Methionin homologue (comprising K (SH)), homocysteine and homoserine, and when existing, it will replace x ¹⁰, x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁷, x ¹⁹, x ²⁰, x ²¹, x ²⁴, x ²⁶, x ²⁷, x ²⁸, x ³², x ³³, x ³⁴, x ³⁵, x ³⁶, x ³⁷, x ³⁸, x ³⁹Or x ⁴⁰One of.

In some aspects, the invention provides the agent of GA target, the agent of described GA target comprises the peptide that comprises with the basic homologous sequence of following sequence:

R ¹-H ¹Aib ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹V ¹⁰S ¹¹S ¹²Y ¹³x ¹⁴E ¹⁵x ¹⁶Q ¹⁷A ¹⁸x ¹⁹x ²⁰E ²¹F ²²I ²³A ²⁴x ²⁵L ²⁶x ²⁷x ²⁸x ²⁹R ³⁰-R ²

X wherein ¹⁴Be G, C, F, Y, W or L, x ¹⁶Be K, D, E or G, x ¹⁹Be L, I, V or A, x ²⁰Be Orn, R or K, x ²⁵Be W or F, x ²⁷Be I or V, x ²⁸Be R or K, and x ²⁹Be Aib or G.

R ¹-H ¹Aib ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹L ¹⁰S ¹¹K ¹²Q ¹³M ¹⁴E ¹⁵E ¹⁶E ¹⁷A ¹⁸V ¹⁹R ²⁰L ²¹F ²²I ²³E ²⁴W ²⁵L ²⁶K ²⁷N ²⁸G ²⁹G ³⁰P ³¹S ³²S ³³G ³⁴A ³⁵P ³⁶P ³⁷P ³⁸S ³⁹-R ²。

In some aspects, connect residue and be selected from K, Y, T and Methionin homologue (comprising K (SH)).Described connection residue can be K (L), and wherein K (L) is the lysine residue that links to each other with joint L, and wherein L can form covalent linkage with the amino acid side chain in the antibody combining site.

In whole specification sheets, claim and accompanying drawing and sequence list, adopt " (L) " to represent and the joint that links to each other at preceding residue covalency.When describing the amino-acid residue leucine, use monamino acid coding " L ".Butt junction " (L) " use bracket and to leucine " L " do not exist bracket with and the context that uses can make those skilled in the art avoid obscuring between two terms.

Connect residue and can be selected from x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁷, x ¹⁹, x ²⁰, x ²¹, x ²⁴, x ²⁷, x ²⁸, x ³², x ³⁴, x ³⁸Hold with C.Connect residue and can be selected from x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁹, x ²⁰, x ²¹, x ²⁷, x ²⁸, x ³²And x ³⁴Connect residue and can be selected from x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁹, x ²⁰And x ²¹Connect residue and can be selected from x ¹³, x ¹⁴, x ¹⁶, x ¹⁹, x ²⁰And x ²¹x ¹⁴Can be to connect residue.

Of the present invention aspect some, R ¹Be C (O) CH ₃, thereby acetylize the aminoterminal of GA target agent.

Of the present invention aspect some, R ²Be NH ₂, thereby amidation the carboxyl terminal of GA target agent.

In some embodiments, the invention provides the GA target compound, described GA target compound comprises the peptide that comprises with the sequence of following sequence homology:

Hx ²E?G?T?F?T?S?D?x ¹⁰x ¹¹x ¹²x ¹³x ¹⁴Ex ¹⁶x ¹⁷Ax ¹⁹x ²⁰x ²¹Fx ²³x ²⁴x ²⁵x ²⁶x ²⁷x ²⁸x ²⁹x ³⁰x ³¹x ³²x ³³x ³⁴x ³⁵x ³⁶x ³⁷x ³⁸x ³⁹x ⁴⁰

Wherein:

x ²Be such as blocking groups such as Aib, A, S, T, V, L, I or D-Ala, x ¹⁰Be V, L, I or A, x ¹¹Be linking group or S, x ¹²Be linking group, S or K, x ¹³Be linking group, Q or Y, x ¹⁴Be linking group, G, C, F, Y, W, M or L, x ¹⁶Be linking group, K, D, E or G, x ¹⁷Be linking group, E or Q, x ¹⁹Be linking group, L, I, V or A, x ²⁰Be linking group, Orn, K (SH), R or K, x ²¹Be linking group, L or E, x ²³Be linking group, I or L, x ²⁴Be linking group, A or E, x ²⁵Be linking group or aromatic residues, x ²⁶Be linking group, L or I, x ²⁷Be linking group, I, K or V, x ²⁸Be linking group, R, Orn, N or K, x ²⁹Be linking group, Aib or G, x ³⁰Be linking group, any amino acid or G, x ³¹Be linking group, P, K (SH) or disappearance, x ³²Be linking group, S or disappearance, x ³³Be linking group, S or disappearance, x ³⁴Be linking group, G or disappearance, x ³⁵Be linking group, A or disappearance, x ³⁶Be linking group, P or disappearance, x ³⁷Be linking group, P or disappearance, x ³⁸Be linking group, P or disappearance, x ³⁹Be linking group, S or disappearance, x ⁴⁰Be linking group or disappearance, thereby described GA target compound contains a linking group, this linking group comprises the nucleophilic side chain that is selected from K, R, C, T and S.

Connecting residue can be K.

The N end can be by end-blocking (uncapped).

Connect residue side chain can with antibody combining site directly or through intermediate head and covalently bound.In some embodiments, the side chain that connects residue is direct or through intermediate head and covalently bound with antibody combining site.

X in some embodiments ²⁶Be L.X in some embodiments ¹¹Be S.X in some embodiments ²⁵Be W or F.X in some embodiments ²⁵Be W.x ²Can be Aib.

Aspect some, present invention includes the GA target compound of the present invention, described GA target compound comprises the peptide that comprises with the sequence of following sequence homology:

H?Aib?E?G?T?F?T?S?D?x ¹⁰S?x ¹²x ¹³x ¹⁴Ex ¹⁶x ¹⁷Ax ¹⁹x ²⁰x ²¹Fx ²³x ²⁴x ²⁵Lx ²⁷x ²⁸x ²⁹x ³⁰x ³¹x ³²x ³³x ³⁴x ³⁵x ³⁶x ³⁷x ³⁸x ³⁹。

In some aspects, present invention includes the GA target compound that comprises peptide, described GA target compound comprises the peptide that comprises with the sequence of following sequence homology:

H ¹x ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹L ¹⁰S ¹¹K ¹²Q ¹³M ¹⁴E ¹⁵E ¹⁶E ¹⁷A ¹⁸V ¹⁹R ²⁰L ²¹F ²²I ²³E ²⁴x ²⁵L ²⁶K ²⁷N ²⁸G ²⁹G ³⁰P ³¹S ³²S ³³G ³⁴A ³⁵P ³⁶P ³⁷P ³⁸S ³⁹x ⁴⁰

Wherein:

x ²Be such as blocking groups such as Aib, A, S, T, V, L, I or D-Ala,

x ²⁵Be to connect residue or aromatic residues,

From P ³¹To S ³⁹One or more residues may lack,

x ⁴⁰Be to connect residue or disappearance, and

S ¹¹To x ⁴⁰One of residue be the connection residue that comprises the side chain that is suitable for forming covalent linkage, described connection residue is selected from K, R, C, T and S.

In some embodiments, GA target of the present invention agent comprises tryptophane cage (Trp-cage) and comprises peptide sequence, described peptide sequence with comprise residue P at least ³¹S ³²S ³³G ³⁴A ³⁵P ³⁶P ³⁷P ³⁸And S ³⁹The basic homology of sequence.In other embodiments, one or more residues or all the tryptophane cages that comprises the tryptophane cage all lacks from the agent of described GA target.

Connect residue and can be used to replace S ¹¹, K ¹², Q ¹³, M ¹⁴, E ¹⁶, E ¹⁷, V ¹⁹, R ²⁰, L ²¹, I ²³, E ²⁴, L ²⁶, K ²⁷, N ²⁸, G ²⁹And G ³⁰One of, or P ³¹, S ³², S ³³, G ³⁴, A ³⁵, P ³⁶, P ³⁷, P ³⁸One of, or S ³⁹, or X ⁴⁰The example of these embodiments is SEQ IDNO:3, SEQ ID NO:172, SEQ ID NO:4, SEQ ID NO:173, SEQ ID NO:115, SEQ ID NO:114, SEQ ID NO:113, SEQ ID NO:169 SEQ ID NO:112, SEQID NO:111, SEQ ID NO:110, SEQ ID NO:109, SEQ ID NO:108, SEQ IDNO:107, SEQ ID NO:106, SEQ ID NO:105, SEQ ID NO:104, SEQ IDNO:103, SEQ ID NO:170, SEQ ID NO:102, SEQ ID NO:168, SEQ IDNO:101, SEQ ID NO:100, SEQ ID NO:99, SEQ ID NO:31, SEQ IDNO:30, SEQ ID NO:29, SEQ ID NO:28, SEQ ID NO:27, SEQ ID NO:26, SEQ ID NO:25, SEQ ID NO:24, SEQ ID NO:23, SEQ ID NO:22, SEQID NO:21, SEQ ID NO:20, SEQ ID NO:19, SEQ ID NO:18, SEQ IDNO:17, SEQ ID NO:16, SEQ ID NO:15, SEQ ID NO:14 and SEQ ID NO:5.

The example of these embodiments also has SEQ ID NO:32, SEQ ID NO:34, SEQ IDNO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ IDNO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ IDNO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ IDNO:75 and SEQ ID NO:76.

In some embodiments, connect residue and can be used to replace K ¹², Q ¹³, M ¹⁴, E ¹⁶, E ¹⁷, V ¹⁹, R ²⁰, L ²¹, I ²³, E ²⁴, L ²⁶, K ²⁷And N ²⁸One of.The example of these embodiments is SEQ ID NO:169, SEQ ID NO:112, SEQ ID NO:111, SEQ IDNO:110, SEQ ID NO:109, SEQ ID NO:108, SEQ ID NO:107, SEQ IDNO:106, SEQ ID NO:105, SEQ ID NO:104, SEQ ID NO:103, SEQ IDNO:170, SEQ ID NO:102, SEQ ID NO:28, SEQ ID NO:27, SEQ IDNO:26, SEQ ID NO:25, SEQ ID NO:24, SEQ ID NO:23, SEQ ID NO:22, SEQ ID NO:21, SEQ ID NO:20, SEQ ID NO:19, SEQ ID NO:18 and SEQID NO:5.

Connect residue and can be used to replace I ²³The example of these embodiments is SEQ ID NO:21 and SEQ ID NO:105.

Connect residue and can be used to replace L ²⁶The example of these embodiments is SEQ ID NO:19 and SEQ ID NO:103.

Connecting residue can be K ¹²The example of these embodiments is SEQ ID NO:5.

In some embodiments, connect residue and can be used to replace Q ¹³, M ¹⁴, E ¹⁶, E ¹⁷, V ¹⁹, R ²⁰, L ²¹And E ²⁴One of.The example of these embodiments is SEQ ID NO:112, SEQID NO:111, SEQ ID NO:110, SEQ ID NO:109, SEQ ID NO:108, SEQ IDNO:107, SEQ ID NO:106, SEQ ID NO:104, SEQ ID NO:28, SEQ IDNO:27, SEQ ID NO:26, SEQ ID NO:25, SEQ ID NO:24, SEQ ID NO:23, SEQ ID NO:22 and SEQ ID NO:20.

Connect residue and can be used to replace Q ¹³The example of these embodiments is SEQ ID NO:28 and SEQ ID NO:112.

In some embodiments, connect residue and can be used to replace M ¹⁴, E ¹⁶, E ¹⁷, V ¹⁹, R ²⁰, L ²¹And E ²⁴One of.The example of these embodiments is SEQ ID NO:111, SEQ IDNO:110, SEQ ID NO:109, SEQ ID NO:108, SEQ ID NO:107, SEQ IDNO:106, SEQ ID NO:104, SEQ ID NO:27, SEQ ID NO:26, SEQ IDNO:25, SEQ ID NO:24, SEQ ID NO:23, SEQ ID NO:22 and SEQ IDNO:20.

Connect residue and can be E ²⁴The example of these embodiments is SEQ ID NO:20 and SEQID NO:104.

In some embodiments, connect residue and can be used to replace M ¹⁴, E ¹⁶, E ¹⁷, V ¹⁹, R ²⁰And L ²¹One of.The example of these embodiments is SEQ ID NO:111, SEQ IDNO:110, SEQ ID NO:109, SEQ ID NO:108, SEQ ID NO:107, SEQ IDNO:106, SEQ ID NO:27, SEQ ID NO:26, SEQ ID NO:25, SEQ IDNO:24, SEQ ID NO:23 and SEQ ID NO:22.

Connect residue and can be used to replace M ¹⁴The example of these embodiments is SEQ IDNO:27 and SEQ ID NO:111.

Connect residue and can be used to replace E ¹⁶The example of these embodiments is SEQ ID NO:26 and SEQ ID NO:110.

Connect residue and can be used to replace E ¹⁷The example of these embodiments is SEQ ID NO:25 and SEQ ID NO:109.

Connect residue and can be used to replace V ¹⁹The example of these embodiments is SEQ ID NO:24 and SEQ ID NO:108.

Connect residue and can be used to replace R ²⁰The example of these embodiments is SEQ ID NO:23 and SEQ ID NO:107.

Connect residue and can be used to replace L ²¹The example of these embodiments is SEQ ID NO:22 and SEQ ID NO:106.

In some embodiments, GA target of the present invention agent comprises the tryptophane cage and comprises peptide sequence, described peptide sequence with comprise residue P at least ³¹S ³²S ³³G ³⁴A ³⁵P ³⁶P ³⁷P ³⁸And S ³⁹The basic homology of sequence.In other embodiments, one or more or all tryptophane cages all lack from the agent of described GA target.

H ¹x ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹x ¹⁰x ¹¹x ¹²x ¹³x ¹⁴E ¹⁵x ¹⁶x ¹⁷Ax ¹⁹x ²⁰x ²¹F ²²x ²³x ²⁴x ²⁵x ²⁶x ²⁷x ²⁸x ²⁹x ³⁰x ³¹x ³²x ³³x ³⁴x ³⁵x ³⁶x ³⁷x ³⁸x ³⁹x ⁴⁰，

Wherein:

x ²Be such as blocking groups such as Aib, A, S, T, V, L or I, x ¹⁰Be V, L, I or A, x ¹¹Be to connect residue or S, x ¹²Be to connect residue, S or K, x ¹³Be to connect residue or Y, x ¹⁴Be to connect residue, G, C, F, Y, W or L, x ¹⁶Be to connect residue, K, D, E or G, x ¹⁷Be to connect residue or Q, x ¹⁹Be to connect residue, L, I, V or A, x ²⁰Be to connect residue, Orn, K (SH), R or K, x ²¹Be to connect residue or E, x ²³Be to connect residue or I, x ²⁴Be to connect residue or A, x ²⁵Be to connect residue or aromatic residues, x ²⁶Be to connect residue or L, x ²⁷Be to connect residue, I or V, x ²⁸Be to connect residue, R, Orn or K, x ²⁹Be to connect residue, Aib or G, x ³⁰Be to connect residue or G, x ³¹Be to connect residue, P, K (SH) or disappearance, x ³²Be to connect residue, S or disappearance, x ³³Be to connect residue, S or disappearance, x ³⁴Be to connect residue, G or disappearance, x ³⁵Be to connect residue, A or disappearance, x ³⁶Be to connect residue, P or disappearance, x ³⁷Be to connect residue, P or disappearance, x ³⁸Be to connect residue, P or disappearance, x ³⁹Be to connect residue, S or disappearance, and x ⁴⁰Be to connect residue or disappearance,

Thereby described GA target compound contains a connection residue that comprises the nucleophilic side chain, and described connection residue is selected from K, R, C, T and S.

In some embodiments, x ²Be Aib.In some embodiments, x ³¹Be Aib.

In some embodiments, x ¹⁶Be E.In some embodiments, x ¹⁹Be V.

H ¹Aib ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹x ¹⁰x ¹¹x ¹²x ¹³x ¹⁴E ¹⁵E ¹⁶x ¹⁷AV ¹⁹x ²⁰x ²¹F ²²x ²³x ²⁴x ²⁵x ²⁶x ²⁷x ²⁸x ²⁹x ³⁰Aib ³¹x ³²x ³³x ³⁴x ³⁵x ³⁶x ³⁷x ³⁸x ³⁹x ⁴⁰

In some embodiments, the present invention comprises the GA target compound, and described GA target compound comprises and the basic homologous sequence of following sequence:

H ¹Aib ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹V ¹⁰S ¹¹S ¹²Y ¹³L ¹⁴E ¹⁵E ¹⁶Q ¹⁷A ¹⁸V ¹⁹K ²⁰E ²¹F ²²I ²³A ²⁴W ²⁵L ²⁶I ²⁷K ²⁸G ²⁹R ³⁰Aib ³¹S ³²S ³³G ³⁴A ³⁵P ³⁶P ³⁷P ³⁸S ³⁹x ⁴⁰，

Wherein from Aib ³¹To S ³⁹One or more residues may lack and x ⁴⁰Be to connect residue or disappearance, and wherein from S ¹¹To x ⁴⁰One of residue be the connection residue that comprises the side chain that is suitable for forming covalent linkage, described connection residue is selected from K, R, C, T and S.The example of these embodiments is SEQ ID NO:57, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQID NO:71 and SEQ ID NO:72.

H ¹x ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹V ¹⁰S ¹¹S ¹²Y ¹³L ¹⁴E ¹⁵G ¹⁶Q ¹⁷A ¹⁸A ¹⁹K ²⁰E ²¹F ²²I ²³A ²⁴x ²⁵L ²⁶V ²⁷K ²⁸G ²⁹R ³⁰P ³¹S ³²S ³³G ³⁴A ³⁵P ³⁶P ³⁷P ³⁸S ³⁹x ⁴⁰

Wherein:

x ²Be such as blocking groups such as Aib, A, S, T, V, L or I,

x ²⁵Be to connect residue or aromatic residues,

From P ³¹To S ³⁹One or more residues may lack,

x ⁴⁰Be to connect residue or disappearance, and

Wherein from S ¹¹To x ⁴⁰One of residue be the connection residue that comprises the nucleophilic side chain, described connection residue is selected from K, R, C, T and S.

The example of these embodiments is SEQ ID NO:32, SEQ ID NO:33, SEQ IDNO:34, SEQ ID NO:35, SEQ ID NO:36 and SEQ ID NO:37.

In some embodiments, GA target of the present invention agent comprises the tryptophane cage and comprises peptide sequence, described peptide sequence with comprise residue P at least ³¹S ³²S ³³G ³⁴A ³⁵P ³⁶P ³⁷P ³⁸And S ³⁹The basic homology of sequence.In other embodiments, one or more residues or all the tryptophane cages that comprises the tryptophane cage all lacks from the agent of described GA target.

Connect residue and can be K.

The N end can be by end-blocking.

The side chain that connects residue can be direct or covalently bound through intermediate head with antibody combining site.In some embodiments, the side chain of connection residue and antibody combining site are direct or covalently bound through intermediate head.

In some embodiments, these peptides are selected from GA target compound as described herein, include but not limited to

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：3)

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：4)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：5)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGG-R ²(SEQ?ID?NO：6)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKN-R ²(SEQ?ID?NO：7)

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKN-R ²(SEQ?ID?NO：8)

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKN-R ²(SEQ?ID?NO：9)

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：10)

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：11)

R ¹-HAibEGTFTSDLSK(Ac)QMEEEAVRLFIEWLK(Ac)NGGPSSGAPPPS-R ²(SEQ?ID?NO：12)

R ¹-HAibEGTFTSDLSK (benzoyl) QMEEEAVRLFIEWLK (benzoyl) NGGPSSGAPPPS-R ²(SEQ ID NO:13)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPKS-R ²(SEQ?ID?NO：14)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAKPPS-R ²(SEQ?ID?NO：15)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSKAPPPS-R ²(SEQ?ID?NO：16)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPKSGAPPPS-R ²(SEQ?ID?NO：17)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKKGGPSSGAPPPS-R ²(SEQ?ID?NO：18)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWKKNGGPSSGAPPPS-R ²(SEQ?ID?NO：19)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIKWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：20)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFKEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：21)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)

R ¹-HAibEGTFTSDLSKQMEEEAVKLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)

R ¹-HAibEGTFTSDLSKQMEEEAKRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)

R ¹-HAibEGTFTSDLSKQMEEKAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：25)

R ¹-HAibEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)

R ¹-HAibEGTFTSDLSKQMEKEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)

R ¹-HAibEGTFTSDLSKQKEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)

R ¹-HAibEGTFTSDLSKKMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：28)

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)

R ¹-HAibEGTFTSDLKKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：29)

R ¹-HAibEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)

R ¹-HAibEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK-R ²(SEQ?ID?NO：30)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK(SH)-R ²(SEQ?ID?NO：114)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSS-R ²(SEQ?ID?NO：31)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGR-R ²(SEQ?ID?NO：32)

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：33)

R ¹-HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：34)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：35)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibRK-R ²(SEQ?ID?NO：36)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：37)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)

R ¹-HAibEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)

R ¹-HAibEGTFTSDVSSYGEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：40)

R ¹-HAibEGTFTSDVSSYCEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：41)

R ¹-HAibEGTFTSDVSSYFEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：42)

R ¹-HAibEGTFTSDVSSYYEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：43)

R ¹-HAibEGTFTSDVSSYWEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：44)

R ¹-HAibEGTFTSDVSSYLEEQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：45)

R ¹-HAibEGTFTSDVSSYLEDQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：46)

R ¹-HAibEGTFTSDVSSYLEKQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：47)

R ¹-HAibEGTFTSDVSSYLEGQAVKEFIAWLVKAibR-R ²(SEQ?ID?NO：48)

R ¹-HAibEGTFTSDVSSYLEGQAIKEFIAWLVKAibR-R ²(SEQ?ID?NO：49)

R ¹-HAibEGTFTSDVSSYLEGQALKEFIAWLVKAibR-R ²(SEQ?ID?NO：50)

R ¹-HAibEGTFTSDVSSYLEGQAAREFIAWLVKAibR-R ²(SEQ?ID?NO：51)

R ¹-HAibEGTFTSDVSSYLEGQAAOrnEFIAWLVKAibR-R ²(SEQ?ID?NO：52)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAFLVKAibR-R ²(SEQ?ID?NO：53)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLIKAibR-R ²(SEQ?ID?NO：54)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVRAibR-R ²(SEQ?ID?NO：55)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVOrnAibR-R ²(SEQ?ID?NO：56)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：57)

R ¹-HAibEGTFTSDVSSYFEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：58)

R ¹-HAibEGTFTSDVSSYYEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：59)

R ¹-HAibEGTFTSDVSSYWEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：60)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIRAibR-R ²(SEQ?ID?NO：61)

R ¹-HAibEGTFTSDVSSYLEEQAVREFIAWLIRAibR-R ²(SEQ?ID?NO：62)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：63)

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：171)

R ¹-HAibEGTFTSDKSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：64)

R ¹-HAibEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：116)

R ¹-HAibEGTFTSDVSKYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：65)

R ¹-HAibEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：117)

R ¹-HAibEGTFTSDVSSYKEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：66)

R ¹-HAibEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：118)

R ¹-HAibEGTFTSDVSSYLEKQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：67)

R ¹-HAibEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：119)

R ¹-HAibEGTFTSDVSSYLEEQKVKEFIAWLIKAibR-R ²(SEQ?ID?NO：68)

R ¹-HAibEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAibR-R ²(SEQ?ID?NO：120)

R ¹-HAibEGTFTSDVSSYLEEQAVKEKIAWLIKAibR-R ²(SEQ?ID?NO：69)

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAibR-R ²(SEQ?ID?NO：121)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIKWLIKAibR-R ²(SEQ?ID?NO：70)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIK(SH)WLIKAibR-R ²(SEQ?ID?NO：122)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWKIKAibR-R ²(SEQ?ID?NO：71)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWK(SH)IKAibR-R ²(SEQ?ID?NO：123)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK-R ²(SEQ?ID?NO：72)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：124)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK(Ac)AibR-R ²(SEQ?ID?NO：73)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK (benzoyl) AibR-R ²(SEQ ID NO:74)

R ¹-H (anti--the 3-caproyl) AibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ ID NO:75)

R ¹-H (3-aminophenyl ethanoyl) AibEGTFTSDVSSYLEEQAVKEFIAWLIKAib R-R ²(SEQ ID NO:76)

R ²Be OH, NH ₂, NH (CH ₃), NHCH ₂CH ₃, NHCH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₃, NHCH ₂CH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₂CH ₃, NHC ₆H ₅, NHCH ₂CH ₂OCH ₃, NHOCH ₃, NHOCH ₂CH ₃, carboxyl-protecting group, lipid is fatty acid-based or sugared.

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVRGR(SEQ?ID?NO：125)

R ¹-HAEGTFTSDVSSYLEGQAAREFIAWLVRGRK(SEQ?ID?NO：126)

R ¹-HAEGTFTSDVSSYLEGQAAREFIAWLVRGK(SEQ?ID?NO：127)

R ¹-HAibEGTFTSDVSSYLEAibQAAKEFIAWLVKAibR(SEQ?ID?NO：128)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibR(SEQ?ID?NO：35)

R ¹-HAibEGTFTSDVSSYLEAibQAAKEFIAWLVKGR(SEQ?ID?NO：129)

R ¹-HAibEGTFTSDVSSYLEAibQAAREFIAWLVRAibRK(SEQ?ID?NO：130)

R ¹-HAibEGTFTSDVSSYLEGQAAREFIAWLVRAibRK(SEQ?ID?NO：131)

R ¹-HAibEGTFTSDVSSYLEAibQAAREFIAWLVRGRK(SEQ?ID?NO：132)

R ¹-HAibEGTFTSDVSSYLEAibQAAREFIAWLVKAibR(SEQ?ID?NO：133)

R ¹-HAibEGTFTSDVSSYLEGQAAREFIAWLVKGRK(SEQ?ID?NO：134)

R ¹-HAibEGTFTSDVSSYLEAibQAAREFIAWLVKGRK(SEQ?ID?NO：135)

R ¹-HAibEGTFTSDVSSYLEAibQAAKEFIAWLVRAibR(SEQ?ID?NO：136)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVRAibRK(SEQ?ID?NO：137)

R ¹-HAibEGTFTSDVSSYLEAibQAAKEFIAWLVRGRK(SEQ?ID?NO：138)

R ¹-HAibEGTFTSDVSSYLEAibQAAKEFIAWLVKAibRAK(SEQ?ID?NO：139)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibRAK(SEQ?ID?NO：140)

R ¹-HAibEGTFTSDVSSYLEAibQAAKEFIAWLVKGRAK(SEQ?ID?NO：141)

R ¹-HAibEGTFTSDVSSYLEAibQAAKEFIAWLVKAibRK(SEQ?ID?NO：142)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibRK(SEQ?ID?NO：36)

R ¹-HAibEGTFTSDVSSYLEAibQAAKEFIAWLVKGRK(SEQ?ID?NO：143)

R ¹-H(D-Ala)EGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SEQ?ID?NO：144)

R ¹-HAibEGTFTSDVSSYLEAibQAAibKEFIAWLVKGRK(SEQ?ID?NO：145)

R ¹-HAibEGTFTSDVSSYLEEEAAREFIEWLVRGRK(SEQ?ID?NO：146)

Wherein:

R ¹Disappearance or CH ₃, C (O) CH ₃, C (O) CH ₂CH ₃, C (O) CH ₂CH ₂CH ₃Or C (O) CH (CH ₃) CH ₃And

In an embodiment of the invention, described GA target compound comprises the sequence that has with the amino acid identity of SEQID NO:1 or SEQ ID NO:2 at least 80%

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR(SEQ?ID?NO：1)[Glp-1]

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS(SEQ?ID?NO：2)[Exendin-4]

Described GA target compound can comprise the aminoacid sequence of following formula:

X ¹X ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹X ¹⁰S ¹¹X ¹²X ¹³X ¹⁴E ¹⁵X ¹⁶X ¹⁷A ¹⁸X ¹⁹X ²⁰X ²¹F ²²I ²³X ²⁴W ²⁵L ²⁶X ²⁷X ²⁸X ²⁹X ³⁰X ³¹X ³²X ³³X ³⁴X ³⁵X ³⁶X ³⁷X ³⁸X ³⁹X ⁴⁰

Wherein:

X ¹Be L-Histidine, D-Histidine, deamination Histidine, the amino Histidine of 2-, beta-hydroxy Histidine, high Histidine, N α-ethanoyl Histidine, α-methyl fluoride Histidine, Alpha-Methyl Histidine, 3-pyridyl L-Ala, 2-pyridyl L-Ala or 4-pyridyl L-Ala; X ²Be A, D-Ala, G, V, L, I, K, Aib, (the amino cyclopropyl of 1-) formic acid, (the amino cyclobutyl of 1-) formic acid, 1-amino cyclopentyl) formic acid, (1-aminocyclohexyl) formic acid, (the amino suberyl of 1-) formic acid or (the amino ring of 1-octyl group) formic acid; X ¹⁰Be V or L; X ¹²Be S, K or R, X ¹³Be Y or Q; X ¹⁴Be L or M; X ¹⁶Be G, E or Aib; X ¹⁷Be Q, E, K or R; X ¹⁹Be A or V; X ²⁰Be K, E or A; X ²¹Be E or L; X ²⁴Be A, E or R; X ²⁷Be V or K; X ²⁸Be K, E, N or R; X ²⁹Be G or R; X ³⁰Be R, G or K; X ³¹Be G, A, E, P, K, acid amides or disappearance; X ³²Be K, S, acid amides or disappearance; X ³³Be S, K, acid amides or disappearance; X ³⁴Be G, acid amides or disappearance; X ³⁵Be A, acid amides or disappearance; X ³⁶Be P, acid amides or disappearance; X ³⁷Be P, acid amides or disappearance; X ³⁸Be P, acid amides or disappearance; X ³⁹Be S, acid amides or disappearance; X ⁴⁰Be acid amides or disappearance;

Condition is if X ³², X ³³, X ³⁴, X ³⁵, X ³⁶, X ³⁷, X ³⁸, X ³⁹Or X ⁴⁰Disappearance then each downstream amino-acid residue also lacks.

In yet another embodiment of the present invention, GA target compound of the present invention can comprise the aminoacid sequence of following formula:

X ¹X ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹V ¹⁰S ¹¹X ¹²Y ¹³L ¹⁴E ¹⁵X ¹⁶X ¹⁷A ¹⁸A ¹⁹X ²⁰E ²¹F ²²I ²³X ²⁴W ²⁵L ²⁶V ²⁷X ²⁸X ²⁹X ³⁰X ³¹X ³²

X wherein ¹Be L-Histidine, D-Histidine, deamination Histidine, the amino Histidine of 2-, beta-hydroxy Histidine, high Histidine, N α-ethanoyl Histidine, α-methyl fluoride Histidine, Alpha-Methyl Histidine, 3-pyridyl L-Ala, 2-pyridyl L-Ala or 4-pyridyl L-Ala; X ²Be A, D-Ala, G, V, L, I, K, Aib, (the amino cyclopropyl of 1-) formic acid, (the amino cyclobutyl of 1-) formic acid, 1-amino cyclopentyl) formic acid or (1-aminocyclohexyl) formic acid, (the amino suberyl of 1-) formic acid or (the amino ring of 1-octyl group) formic acid; X ¹²Be S, K or R; X ¹⁶Be G, E or Aib; X ¹⁷Be Q, E, K or R; X ²⁰Be K, E or T; X ²⁴Be A, E or R; X ²⁸Be K, E or R; X ²⁹Be G or Aib; X ³⁰Be R or K; X ³¹Be G, A, E or K; X ³²Be K, acid amides or disappearance.

In yet another embodiment of the present invention, the agent of described GA target is protected two peptidyl aminopeptidase IV.In yet another embodiment of the present invention, with the given pace hydrolysis, described given pace is lower than the speed of using DPP-IV hydrolysis disclosed herein to test the SEQ ID NO:1 hydrolysis of carrying out to the agent of described GA target by DPP-IV.In yet another embodiment of the present invention, the A of described GA target agent ²By another amino-acid residue (X ²) replace.In some embodiments, X ²Be Aib.In yet another embodiment of the present invention, X ¹Be selected from D-Histidine, deamination Histidine, the amino Histidine of 2-, beta-hydroxy Histidine, high Histidine, N α-ethanoyl Histidine, α-methyl fluoride Histidine, Alpha-Methyl Histidine, 3-pyridyl L-Ala, 2-pyridyl L-Ala and 4-pyridyl L-Ala.

In yet another embodiment of the present invention, the agent of described GA target is compared with SEQ ID NO:1 or SEQ ID NO:2 to comprise and is no more than 12 by the amino-acid residue of exchange, interpolation or disappearance.In yet another embodiment of the present invention, the agent of described GA target is compared with SEQ ID NO:1 or SEQ ID NO:2 to comprise and is no more than 6 by the amino-acid residue of exchange, interpolation or disappearance.In yet another embodiment of the present invention, the agent of described GA target is compared with SEQ ID NO:1 or SEQ ID NO:2 to comprise and is no more than 4 by the amino-acid residue of exchange, interpolation or disappearance.In yet another embodiment of the present invention, the agent of described GA target is compared with SEQ ID NO:1 or SEQ ID NO:2 to comprise and is no more than 2 by the amino-acid residue of exchange, interpolation or disappearance.In yet another embodiment of the present invention, the agent of described GA target comprises that to be no more than 4 be not by genetic code amino acids coding residue.

In yet another embodiment of the present invention, described GA target compound is:

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPS SGAPPPSKKKKKK-acid amides (SEQ ID NO:147).

In some embodiments, the invention provides and the agent of the basic homologous GA of GLP-1 target.GA target of the present invention agent can with GLP-1 (SEQ ID NO:1) at least 95% homology.GA target of the present invention agent can with GLP-1 at least 90% homology.GA target of the present invention agent can with GLP-1 at least 80% homology.GA target of the present invention agent can with GLP-1 at least 70% homology.GA target of the present invention agent can with GLP-1 at least 60% homology.GA target of the present invention agent can with GLP-1 at least 53% homology.GA target of the present invention agent can with GLP-1 at least 50% homology.

In some embodiments, the invention provides basic homologous GA target agent with Exendin-4 (SEQ ID NO:2).GA target of the present invention agent can with Exendin-4 at least 95% homology.GA target of the present invention agent can with Exendin-4 at least 90% homology.GA target of the present invention agent can with Exendin-4 at least 80% homology.GA target of the present invention agent can with Exendin-4 at least 70% homology.GA target of the present invention agent can with Exendin-4 at least 60% homology.GA target of the present invention agent can with Exendin-4 at least 53% homology.GA target of the present invention agent can with Exendin-4 at least 50% homology.

In some embodiments, provide GA target agent-joint conjugate with formula I:

The agent of L-[GA target] (I)

Wherein:

[agent of GA target] is the peptide agonists of GLP-1R.In some embodiments, [agent of GA target] is the peptide that is selected from GA target compound as described herein, includes but not limited to:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：3)

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：4)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：5)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGG-R ²(SEQ?ID?NO：6)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKN-R ²(SEQ?ID?NO：7)

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKN-R ²(SEQ?ID?NO：8)

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKN-R ²(SEQ?ID?NO：9)

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：10)

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：11)

R ¹-HAibEGTFTSDLSK(Ac)QMEEEAVRLFIEWLK(Ac)NGGPSSGAPPPS-R ²(SEQ?ID?NO：12)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPKS-R ²(SEQ?ID?NO：14)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAKPPS-R ²(SEQ?ID?NO：15)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSKAPPPS-R ²(SEQ?ID?NO：16)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPKSGAPPPS-R ²(SEQ?ID?NO：17)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKKGGPSSGAPPPS-R ²(SEQ?ID?NO：18)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?IDNO：102)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWKKNGGPSSGAPPPS-R ²(SEQ?ID?NO：19)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIKWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：20)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFKEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：21)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)

R ¹-HAibEGTFTSDLSKQMEEEAVKLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)

R ¹-HAibEGTFTSDLSKQMEEEAKRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)

R ¹-HAibEGTFTSDLSKQMEEKAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：25)

R ¹-HAibEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)

R ¹-HAibEGTFTSDLSKQMEKEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)

R ¹-HAibEGTFTSDLSKQKEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)

R ¹-HAibEGTFTSDLSKKMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：28)

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)

R ¹-HAibEGTFTSDLKKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：29)

R ¹-HAibEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)

R ¹-HAibEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK-R ²(SEQ?ID?NO：30)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK(SH)-R ²(SEQ?ID?NO：114)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSS-R ²(SEQ?ID?NO：31)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGR-R ²(SEQ?ID?NO：32)

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：33)

R ¹-HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：34)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：35)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibRK-R ²(SEQ?ID?NO：36)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：37)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)

R ¹-HAibEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)

R ¹-HAibEGTFTSDVSSYGEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：40)

R ¹-HAibEGTFTSDVSSYCEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：41)

R ¹-HAibEGTFTSDVSSYFEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：42)

R ¹-HAibEGTFTSDVSSYYEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：43)

R ¹-HAibEGTFTSDVSSYWEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：44)

R ¹-HAibEGTFTSDVSSYLEEQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：45)

R ¹-HAibEGTFTSDVSSYLEDQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：46)

R ¹-HAibEGTFTSDVSSYLEKQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：47)

R ¹-HAibEGTFTSDVSSYLEGQAVKEFIAWLVKAibR-R ²(SEQ?ID?NO：48)

R ¹-HAibEGTFTSDVSSYLEGQAIKEFIAWLVKAibR-R ²(SEQ?ID?NO：49)

R ¹-HAibEGTFTSDVSSYLEGQALKEFIAWLVKAibR-R ²(SEQ?ID?NO：50)

R ¹-HAibEGTFTSDVSSYLEGQAAREFIAWLVKAibR-R ²(SEQ?ID?NO：51)

R ¹-HAibEGTFTSDVSSYLEGQAAOrnEFIAWLVKAibR-R ²(SEQ?ID?NO：52)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAFLVKAibR-R ²(SEQ?ID?NO：53)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLIKAibR-R ²(SEQ?ID?NO：54)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVRAibR-R ²(SEQ?ID?NO：55)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVOrnAibR-R ²(SEQ?ID?NO：56)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：57)

R ¹-HAibEGTFTSDVSSYFEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：58)

R ¹-HAibEGTFTSDVSSYYEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：59)

R ¹-HAibEGTFTSDVSSYWEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：60)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIRAibR-R ²(SEQ?ID?NO：61)

R ¹-HAibEGTFTSDVSSYLEEQAVREFIAWLIRAibR-R ²(SEQ?ID?NO：62)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：63)

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：171)

R ¹-HAibEGTFTSDKSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：64)

R ¹-HAibEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：116)

R ¹-HAibEGTFTSDVSKYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：65)

R ¹-HAibEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：117)

R ¹-HAibEGTFTSDVSSYKEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：66)

R ¹-HAibEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：118)

R ¹-HAibEGTFTSDVSSYLEKQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：67)

R ¹-HAibEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：119)

R ¹-HAibEGTFTSDVSSYLEEQKVKEFIAWLIKAibR-R ²(SEQ?ID?NO：68)

R ¹-HAibEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAibR-R ²(SEQ?ID?NO：120)

R ¹-HAibEGTFTSDVSSYLEEQAVKEKIAWLIKAibR-R ²(SEQ?ID?NO：69)

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAibR-R ²(SEQ?ID?NO：121)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIKWLIKAibR-R ²(SEQ?ID?NO：70)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIK(SH)WLIKAibR-R ²(SEQ?ID?NO：122)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWKIKAibR-R ²(SEQ?ID?NO：71)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWK(SH)IKAibR-R ²(SEQ?ID?NO：123)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK-R ²(SEQ?ID?NO：72)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：124)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK(Ac)AibR-R ²(SEQ?ID?NO：73)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK (benzoyl) AibR-R ²(SEQ ID NO:74)

R ¹-H (3-aminophenyl ethanoyl) AibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ ID NO:76)

Wherein:

R ¹Disappearance or CH ₃, C (O) CH3, C (O) CH ₂CH ₃, C (O) CH ₂CH ₂CH ₃Or C (O) CH (CH ₃) CH ₃With

R ²Be OH, NH ₂, NH (CH ₃), NHCH ₂CH ₃, NHCH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₃, NHCH ₂CH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₂CH ₃, NHC ₆H ₅, NHCh ₂CH ₂OCH ₃, NHOCH ₃, NHOCH ₂CH ₃, carboxyl-protecting group, lipid is fatty acid-based or sugared;

And can form any C end truncate and analogue from these peptides; And

L is the shank with formula-X-Y-Z, wherein:

X exists alternatively, and is biocompatible polymer, segmented copolymer, C, H, N, O, P, S, halogen (F, Cl, Br, I) or its salt, alkyl, thiazolinyl, alkynyl, oxoalkyl group, oxo thiazolinyl, oxo alkynyl, aminoalkyl group, amino thiazolinyl, amino alkynyl, alkylthio, sulfo-thiazolinyl, sulfo-alkynyl, alkyl acid phosphate, phosphoric acid thiazolinyl or the phosphoric acid alkynyl that links to each other with one of residue that constitutes the agent of GA target;

Y is the recognition group that comprises at least one ring structure that exists alternatively; And

Z be can be covalently bound with the side chain of antibody combining site reactive group; With

Its pharmacologically acceptable salt, steric isomer, tautomer, solvate and prodrug.

In some embodiments, X links to each other with carboxyl terminal, S side chain, K side chain, K (SH) side chain, T side chain or the Y side chain of the agent of GA target.

In others, the invention provides the compound of formula with the following compounds of being selected from:

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(L)NGGPSSGAPPPS-R ²(SEQ?ID?NO：148)

R ¹-HAibEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：149)

R ¹-HAibEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：150)

R ¹-HAibEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：151)

R ¹-HAibEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：164)

R ¹-HAibEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：152)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK(L)-R ²(SEQ?ID?NO：153)

R ¹-HAibEGTFTSDVSSYLEEQAVK(L)EFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：154)

R ¹-HAibEGTFTSDVSSYLEGQAAK(L)EFIAWLVKGR-R ²(SEQ?ID?NO：155)

Wherein

R ²Be OH, NH ₂, NH (CH ₃), NHCH ₂CH ₃, NHCH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₃, NHCH ₂CH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₂CH ₃, NHC ₆H ₅, NHCH ₂CH ₂OCH ₃, NHOCH ₃, NHOCH ₂CH ₃, carboxyl-protecting group, lipid is fatty acid-based or sugared, and

K (L) is the lysine residue covalently bound with joint L.In some embodiments, K (L) is:

Wherein u is 1,2 or 3;

-L-is the shank with formula-X-Y-Z-, wherein:

X is:

Wherein v is 0,1,2 or 3; T is 1,2 or 3, and r is 1 or 2; S is 0,1 or 2;

R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl;

Y is the recognition group that comprises at least one ring structure; With

Z is the reactive group that can form covalent linkage with the amino acid side chain of antibody combining site.

In some embodiments, Y has the optional structure that replaces:

Wherein a, b, c, d and e are carbon or nitrogen independently of one another; F is carbon, nitrogen, oxygen or sulphur; Y links to each other at any two ring position places of enough valence states with Z with X independently; And be no more than four among a, b, c, d, e and the f and be nitrogen simultaneously.

In some embodiments, Z is selected from and replaces 1,3-diketone or acyl group-beta-lactam.

In some embodiments, Z has structure:

Q=0,1,2,3,4 or 5 wherein.In other embodiments, q=1,2 or 3.In some embodiment of the compound of formula I, X is:

-R ²²-P-R ²³-or-R ²²-P-R ²¹-P '-R ²³-

Wherein:

P and P ' are independently selected from the polyoxyalkylene oxide compound (such as polyoxyethylene, the Ju ethyl oxazoline, the poly-N-vinyl pyrrolidone, polyvinyl alcohol, Poly(Hydroxyethyl Methacrylate), poly hydroxy ethyl acrylate and polyacrylamide), on main polymer chain or polymer lateral chain, have amino polyamine (such as polylysine, poly ornithine, poly arginine and polyhistidyl), non-peptide polyamine is (such as poly-amino-benzene ethene, poly-amino acrylates, poly-(N-methylamino acrylate), poly-(N-ethylamino acrylate), poly-(N, N-dimethylamino acrylate), poly-(N, N-diethylamino acrylate), poly-(amino methyl acrylate), poly-(N-methylamino methacrylic ester), poly-(N-ethylamino methacrylic ester), poly-(N, N-dimethylaminomethyl acrylate), poly-(N, N-diethylamino methyl acrylate), polymine), quaternary polyamines is (such as poly-(chlorination N, N, N-trimethylammonium amino acrylates), poly-(methyl chloride acrylamido oxypropyl trimethyl ammonium)), protein-polysaccharide is (such as chondroitin sulfate-A (4-vitriol), chondroitin sulfate-C (6-vitriol) and chondroitin sulfate-B), polypeptide is (such as polyserine, poly-Threonine, the polyglutamic acid amides), natural or synthetic polysaccharide is (such as chitosan, Natvosol) and lipid;

R ²¹, R ²²And R ²³Be independently of one another covalent linkage ,-O-,-S-,-NR ^b-, acid amides, replacement or unsubstituted straight or branched C _1-50Alkylidene group or replacement or unsubstituted straight or branched C _1-50Assorted alkylidene group;

R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl; And

Select R ²¹, R ²²And R ²³Thereby make the backbone length of X remain about 200 atoms or about 200 below the atom.

In some embodiment of the compound of formula I, X links to each other with amino-acid residue in [agent of GA target], and is randomly to replace-R ²²-[CH ₂-CH ₂-O] _t-R ²³-,-R ²²-cycloalkyl-R ²³-,-R ²²-aryl-R ²³-or-R ²²-heterocyclic radical-R ²³-, wherein t is 0～50.

In some embodiment of the compound of formula I, R ²²Be-(CH ₂) _v-,-(CH ₂) _u-C (O)-(CH ₂) _v-,-(CH ₂) _u-C (O)-O-(CH ₂) _v-,-(CH ₂) _u-C (S)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-C (O)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-NR ^b-(CH ₂) _v-,-(CH ₂) _u-O-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-NR ^b-(CH ₂) _v-or-(CH ₂) _u-P (O) (OR ^b)-O-(CH ₂) _v-, wherein u and v are 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently.

In some embodiment of the compound of formula I, R ²¹And R ²³Be independently-(CH ₂) _s-,-(CH ₂) _r-C (O)-(CH ₂) _s-,-(CH ₂) _r-C (O)-O-(CH ₂) _v-,-(CH ₂) _r-C (S)-NR ^b-(CH ₂) _s-,-(CH ₂) _r-C (O)-NR ^b-(CH ₂) _s-,-(CH ₂) _r-NR ^b-(CH ₂) _s-,-(CH ₂) _r-O-(CH ₂) _s-,-(CH ₂) _r-S (O) _0-2-(CH ₂) _s-,-(CH ₂) _r-S (O) _0-2-NR ^b-(CH ₂) _s-or-(CH ₂) _r-P (O) (OR ^b)-O-(CH ₂) _s-, wherein r, s and v are 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently.

In some embodiment of formula I, if if t＞1 or X are-R ²²-[CH ₂-CH ₂-O] _t-R ²³-,-R ²²-cycloalkyl-R ²³,-R ²²-aryl-R ²³-or-R ²²-heterocyclic radical-R ²³-, then Y exists.

According to the exemplary compounds of formula I as shown in Fig. 1 and Fig. 3.

Shown in II, another aspect of the present invention is a kind of GA target compound, and described GA target compound comprises through getting involved joint L ' and the covalently bound GA target agent of antibody combining site.When using this term in this article, the antibody moiety of GA target compound can comprise any other form of whole (total length) antibody, unique antibody fragment or antibody.In one embodiment, described antibody is the humanization form that comprises from the mouse zymohexase antibody of the constant region of human IgG, IgA, IgM, IgD or IgE antibody.In another embodiment, described antibody is to comprise from the variable region of mouse zymohexase antibody with from the chimeric antibody of the constant region of human IgG, IgA, IgM, IgD or IgE antibody.In another embodiment, described antibody is the complete human form that comprises from the mouse zymohexase antibody of the peptide sequence of natural or natural human IgG, IgA, IgM, IgD or IgE antibody.

Antibody-L '-[agent of GA target] (II)

Wherein:

[agent of GA target] is the peptide agonists of GLP-1R.In some embodiments, [agent of GA target] is selected from GA target compound as described herein, includes but not limited to:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：3)

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：4)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：5)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGG-R ²(SEQ?ID?NO：6)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKN-R ²(SEQ?ID?NO：7)

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKN-R ²(SEQ?ID?NO：8)

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKN-R ²(SEQ?ID?NO：9)

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：10)

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：11)

R ¹-HAibEGTFTSDLSK(Ac)QMEEEAVRLFIEWLK(Ac)NGGPSSGAPPPS-R ²(SEQ?ID?NO：12)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPKS-R ²(SEQ?ID?NO：14)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAKPPS-R ²(SEQ?ID?NO：15)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSKAPPPS-R ²(SEQ?ID?NO：16)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPKSGAPPPS-R ²(SEQ?ID?NO：17)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKKGGPSSGAPPPS-R ²(SEQ?ID?NO：18)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWKKNGGPSSGAPPPS-R ²(SEQ?ID?NO：19)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIKWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：20)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFKEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：21)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)

R ¹-HAibEGTFTSDLSKQMEEEAVKLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)

R ¹-HAibEGTFTSDLSKQMEEEAKRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)

R ¹-HAibEGTFTSDLSKQMEEKAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：25)

R ¹-HAibEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)

R ¹-HAibEGTFTSDLSKQMEKEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)

R ¹-HAibEGTFTSDLSKQKEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)

R ¹-HAibEGTFTSDLSKKMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：28)

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)

R ¹-HAibEGTFTSDLKKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：29)

R ¹-HAibEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)

R ¹-HAibEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK-R ²(SEQ?ID?NO：30)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK(SH)-R ²(SEQ?ID?NO：114)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSS-R ²(SEQ?ID?NO：31)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGR-R ²(SEQ?ID?NO：32)

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：33)

R ¹-HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：34)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：35)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibRK-R ²(SEQ?ID?NO：36)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：37)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)

R ¹-HAibEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)

R ¹-HAibEGTFTSDVSSYGEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：40)

R ¹-HAibEGTFTSDVSSYCEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：41)

R ¹-HAibEGTFTSDVSSYFEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：42)

R ¹-HAibEGTFTSDVSSYYEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：43)

R ¹-HAibEGTFTSDVSSYWEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：44)

R ¹-HAibEGTFTSDVSSYLEEQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：45)

R ¹-HAibEGTFTSDVSSYLEDQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：46)

R ¹-HAibEGTFTSDVSSYLEKQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：47)

R ¹-HAibEGTFTSDVSSYLEGQAVKEFIAWLVKAibR-R ²(SEQ?ID?NO：48)

R ¹-HAibEGTFTSDVSSYLEGQAIKEFIAWLVKAibR-R ²(SEQ?ID?NO：49)

R ¹-HAibEGTFTSDVSSYLEGQALKEFIAWLVKAibR-R ²(SEQ?ID?NO：50)

R ¹-HAibEGTFTSDVSSYLEGQAAREFIAWLVKAibR-R ²(SEQ?ID?NO：51)

R ¹-HAibEGTFTSDVSSYLEGQAAOrnEFIAWLVKAibR-R ²(SEQ?ID?NO：52)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAFLVKAibR-R ²(SEQ?ID?NO：53)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLIKAibR-R ²(SEQ?ID?NO：54)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVRAibR-R ²(SEQ?ID?NO：55)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVOrnAibR-R ²(SEQ?ID?NO：56)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：57)

R ¹-HAibEGTFTSDVSSYFEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：58)

R ¹-HAibEGTFTSDVSSYYEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：59)

R ¹-HAibEGTFTSDVSSYWEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：60)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIRAibR-R ²(SEQ?ID?NO：61)

R ¹-HAibEGTFTSDVSSYLEEQAVREFIAWLIRAibR-R ²(SEQ?ID?NO：62)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：63)

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：171)

R ¹-HAibEGTFTSDKSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：64)

R ¹-HAibEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：116)

R ¹-HAibEGTFTSDVSKYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：65)

R ¹-HAibEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：117)

R ¹-HAibEGTFTSDVSSYKEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：66)

R ¹-HAibEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：118)

R ¹-HAibEGTFTSDVSSYLEKQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：67)

R ¹-HAibEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：119)

R ¹-HAibEGTFTSDVSSYLEEQKVKEFIAWLIKAibR-R ²(SEQ?ID?NO：68)

R ¹-HAibEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAibR-R ²(SEQ?ID?NO：120)

R ¹-HAibEGTFTSDVSSYLEEQAVKEKIAWLIKAibR-R ²(SEQ?ID?NO：69)

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAibR-R ²(SEQ?ID?NO：121)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIKWLIKAibR-R ²(SEQ?ID?NO：70)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIK(SH)WLIKAibR-R ²(SEQ?ID?NO：122)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWKIKAibR-R ²(SEQ?ID?NO：71)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWK(SH)IKAibR-R ²(SEQ?ID?NO：123)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK-R ²(SEQ?ID?NO：72)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：124)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK(Ac)AibR-R ²(SEQ?ID?NO：73)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK (benzoyl) AibR-R ²(SEQ ID NO:74)

Wherein:

R ²Be OH, NH ₂, NH (CH ₃), NHCH ₂CH ₃, NHCH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₃, NHCH ₂CH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₂CH ₃, NHC ₆H ₅, NHCH ₂CH ₂OCH ₃, NHOCH ₃, NHOCH ₂CH ₃, carboxyl-protecting group, lipid is fatty acid-based or sugared,

And can form any C end truncate and analogue from these peptides; And

L ' is the shank with formula-X-Y-Z ', wherein:

X is biocompatible polymer or the segmented copolymer that links to each other with one of residue that constitutes the agent of GA target;

Y is the recognition group that comprises at least one ring structure that randomly exists; With

Z is the group covalently bound with the side chain of antibody combining site;

And pharmacologically acceptable salt, steric isomer, tautomer, solvate and prodrug.

In some embodiment of the compound of formula II, X is:

-R ²²-P-R ²³-or-R ²²-P-R ²¹-P '-R ²³-

Wherein:

Select R ²¹, R ²²And R ²³Thereby make the backbone length of X remain about 200 atoms or 200 below the atom.

In some embodiment of the compound of formula II, X links to each other with amino-acid residue in [agent of GA target], and is optional the replacement-R ²²-[CH ₂-CH ₂-O] _t-R ²³-,-R ²²-cycloalkyl-R ²³-,-R ²²-aryl-R ²³-or-R ²²-heterocyclic radical-R ²³-, wherein t is 0～50.

In some embodiment of the compound of formula II, R ²²Be-(CH ₂) _v-,-(CH ₂) _u-C (O)-(CH ₂) _v-,-(CH ₂) _u-C (O)-O-(CH ₂) _v-,-(CH ₂) _u-C (S)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-C (O)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-NR ^b-(CH ₂) _v-,-(CH ₂) _u-O-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-NR ^b-(CH ₂) _v-or-(CH ₂) _u-P (O) (OR ^b)-O-(CH ₂) _v-, wherein u and v are 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently.

In some embodiment of the compound of formula II, R ²¹And R ²³Be independently-(CH ₂) _s-,-(CH ₂) _r-C (O)-(CH ₂) _s-,-(CH ₂) _r-C (O)-O-(CH ₂) _v-,-(CH ₂) _r-C (S)-NR ^b-(CH ₂) _s-,-(CH ₂) _r-C (O)-NR ^b-(CH ₂) _s-,-(CH ₂) _r-NR ^b-(CH ₂) _s-,-(CH ₂) _r-O-(CH ₂) _s-,-(CH ₂) _r-S (O) _0-2-(CH ₂) _s-,-(CH ₂) _r-S (O) _0-2-NR ^b-(CH ₂) _s-or-(CH ₂) _r-P (O) (OR ^b)-O-(CH ₂) _s-, wherein r, s and v are 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently.

In some embodiment of the compound of formula II, [agent of GA target] is the peptide that is selected from following compounds:

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(L’)NGGPSSGAPPPS-R ²(SEQ?ID?NO：156)

R ¹-HAibEGTFTSDLSKQMEEEAVRK(L’)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：157)

R ¹-HAibEGTFTSDLSKQMEEEAVK(L’)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：158)

R ¹-HAibEGTFTSDLSKQMEEEAK(L’)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：159)

R ¹-HAibEGTFTSDLSKQK(L’)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：160)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK(L’)-R ²(SEQ?ID?NO：161)

R ¹-HAibEGTFTSDVSSYLEEQAVK(L’)EFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：162)

R ¹-HAibEGTFTSDVSSYLEGQAAK(L’)EFIAWLVKGR-R ²(SEQ?ID?NO：163)

Wherein

K (L ') be the lysine residue covalently bound with joint L '.In some embodiments, K (L ') is:

Wherein u is 1,2 or 3;

-L '-be shank with formula-X-Y-Z-, wherein:

X is:

Wherein v is 0,1,2 or 3; T is 1,2 or 3; R is 1 or 2; S is 0,1 or 2;

Y is the recognition group that comprises at least one ring structure; With

Z ' comprises the covalently bound attachment portion that links to each other with amino acid side chain in the antibody combining site,

In some embodiments, Y has the optional structure that replaces:

In some embodiments, Z ' has structure:

Wherein q=0,1,2,3,4 or 5 and-N-antibody is meant covalently bound with the amino acid side chain that has amino antibody combining site.In others, q=1,2 or 3.

Shown in formula III, another aspect of the present invention is a kind of GA target compound, and two GA targets agent that wherein can be identical or different links to each other with the antibody combining site covalency.When using this term in this article, the antibody moiety of GA target compound can comprise any other form of whole (total length) antibody, unique antibody fragment or antibody.In one embodiment, described antibody is the humanization form that comprises from the mouse zymohexase antibody of the constant region of human IgG, IgA, IgM, IgD or IgE antibody.In another embodiment, described antibody is to comprise from the variable region of mouse zymohexase antibody with from the chimeric antibody of the constant region of human IgG, IgA, IgM, IgD or IgE antibody.In another embodiment, described antibody is the complete human form that comprises from the mouse zymohexase antibody of the peptide sequence of natural or natural human IgG, IgA, IgM, IgD or IgE antibody:

Antibody [L '-[agent of GA target]] ₂(III)

Wherein [agent of GA target], antibody and L ' define suc as formula II.

The exemplary compounds of formula I such as Fig. 2 and shown in Figure 4.

In some embodiments, provide the diabetes that are used for the treatment of study subject or the method for diabetes associated conditions, described method comprises the GA target compound of described study subject administering therapeutic significant quantity or its medicaments derivative.

In some embodiments, provide the method for the insulin secretion that is used to increase study subject, described method comprises the GA target compound of described study subject administering therapeutic significant quantity or its medicaments derivative.

In some embodiments, provide the method for glucose level that is used to reduce study subject, described method comprises the GA target compound of described study subject administering therapeutic significant quantity or its medicaments derivative.

In some embodiments, provide to be used to generate the GA target compound of medicament and the use of medicaments derivative thereof, described medicament is used for the treatment of diabetes or diabetes associated conditions, or is used to increase insulin secretion or lowering blood glucose level.

Some GA target compound of the present invention comprises:

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)

R ¹-HAibEGTFTSDLSKQMEEEAVKLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)

R ¹-HAibEGTFTSDLSKQMEEEAKRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)

R ¹-HAibEGTFTSDLSKQMEKEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)

R ¹-HAibEGTFTSDLSKQKEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)

Some GA target compound of the present invention comprises:

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)

Some GA target compound of the present invention comprises:

R ¹-HAibEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：149)

R ¹-HAibEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：150)

R ¹-HAibEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：151)

R ¹-HAibEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：164

R ¹-HAibEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：152)

Wherein K (L) is the lysine residue that links to each other with joint L, and wherein L can form covalent linkage with the amino acid side chain of antibody combining site.

Some compound of the present invention comprises:

R ¹-HAibEGTFTSDLSKQMEEEAVRK(L’)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：157)

R ¹-HAibEGTFTSDLSKQMEEEAVK(L’)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：158)

R ¹-HAibEGTFTSDLSKQMEEEAK(L’)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：159)

R ¹-HAibEGTFTSDLSKQMEK(L’)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：165)

R ¹-HAibEGTFTSDLSKQK(L’)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：160)

Wherein K (L ') is the lysine residue that links to each other with joint L ', and wherein L ' can form covalent linkage with the amino acid side chain of antibody combining site.In some embodiments, K (L ') is:

Wherein u is 1,2 or 3;

-L-has one of them joint of formula-X-Y-Z-or formula-X-Y-Z ', wherein:

X is:

Wherein v is 0,1,2 or 3; T is 1,2 or 3, and r is 1 or 2; S is 0,1 or 2;

R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl C _0-6Alkyl;

Y is the recognition group that comprises at least one ring structure that randomly exists; And

Description of drawings

Fig. 1 a and Fig. 1 b have shown respectively according to embodiment of formula I with according to an embodiment of formula II or formula III.

Fig. 2 a and Fig. 2 b have shown respectively according to embodiment of formula I with according to an embodiment of formula II or formula III.

Fig. 3 has shown an embodiment according to formula I.

Fig. 4 has shown an embodiment according to formula II or formula III.

Fig. 5 A and Fig. 5 B have shown the solid phase synthesis of target agent of the present invention-joint conjugate.

Fig. 6 has shown m38c2 (SEQ ID NO:77 and SEQ ID NO:78), h38c2 (SEQID NO:79 and SEQ ID NO:80) and human aminoacid sequence comparison of planting the variable domain that is DPK-9 (SEQ ID NO:81), DP-47 (SEQ ID NO:82), JK4 (SEQ ID NO:83) and JH4 (SEQ ID NO:84).Framework region (FR) and complementary determining region such as Kabat etc. definition.Asterisk has marked between m38c2 and the h38c2 or h38c2 and human difference of planting between the system.

Fig. 7 has shown the various structures that can serve as the joint reactive group.X among the structure A can be N, C or any other heteroatoms.R ' among structure A～C ₁, R ' ₂, R ₃And R ₄Expression comprise for example substituting group of C, H, N, O, P, S, halogen (F, Cl, Br, I) or its salt.These substituting groups can also comprise such as groups such as alkyl, thiazolinyl, alkynyl, oxoalkyl group, oxo thiazolinyl, oxo alkynyl, aminoalkyl group, amino thiazolinyl, amino alkynyl, alkylthio, sulfo-thiazolinyl, sulfo-alkynyl, alkyl acid phosphate, phosphoric acid thiazolinyl or phosphoric acid alkynyls.R ' ₂And R ₃Can be the part of ring structure, as structure B and structure C institute example.The surperficial come-at-able reactive nucleophilic group of structure A～C and antibody combining site (for example, Methionin or cysteine side chain) has formed reversible covalent bonds.For example, if if X is N and R ' ₁And R ₃Form the part of ring structure, then structure A can form reversible covalent bonds with reactive nucleophilic reagent.Structure D～G can form irreversible covalent linkage with the reactive nucleophilic group in the antibody combining site.In these structures, R " ₁And R " ₂Expression C, O, N, halogen or such as leavings groups such as methylsulfonyl or tosyl groups.

Fig. 8 has shown and is applicable to the reaction of the reactive amino of antibody combining site acid side chain and modifies and thereby can serve as the various electrophilic reagents of joint reactive group.Legend: (A) acyl group-beta-lactam; (B) simple diketone; (C) succinimide active ester; (D) maleimide; (E) have the Haloacetamide of joint; (F) halogenated ketone; (G) cyclohexyl diketone; (H) aldehyde.The quirk line is represented the attachment point with joint or target agent remainder.X refers to halogen.

Fig. 9 has shown the addition of compd A～G of nucleophilic (" the nu ") side chain of antibody combining site and Fig. 7.

Figure 10 has shown the addition of compd A～H of the nucleophilic side chain of antibody combining site and Fig. 8.

Figure 11 has shown the synthetic of following compound:

Figure 12 has shown the synthetic of following compound:

Figure 13 has shown the synthetic of following compound:

Figure 14 has shown the synthetic of following compound:

Figure 15 has shown the synthetic of following compound:

Figure 16 has shown the synthetic of following compound:

Figure 17 has shown the synthetic of following compound:

Figure 18 has shown the synthetic of following compound:

Figure 19 has shown the synthetic of following compound:

Figure 20 has shown the synthetic of following compound:

Figure 21 has shown the synthetic of following compound:

Figure 22 has shown the synthetic of following compound:

Figure 23 has shown the synthetic of following compound:

Figure 24 has shown the synthetic of following compound:

Figure 25 has shown the synthetic of following compound:

Figure 26 has shown the synthetic of following compound:

Figure 27 has shown mammalian expression vector PIGG-h38c2.Described 9kb carrier comprises heavy chain γ 1 and the light chain κ expression cassette that is driven by two-way CM promoter construct.

Figure 28 has shown the synthetic of following compound:

Figure 29 has shown the synthetic of 20-atom A ZD maleimide joint:

Figure 30 has shown the synthetic of Methionin that the side chain that is used in the GA target peptide is modified.

Figure 31 has shown GA target agent-joint conjugate synthetic of the GA target peptide that comprises SEQ ID NO:22, and described GA target peptide links to each other with the Lys residue that 20-atom A ZD maleimide joint shown in Figure 29 is modified via side chain in this peptide.

Figure 32 has shown GA target agent-joint conjugate synthetic of the GA target peptide that comprises SEQ ID NO:32, and described GA target peptide links to each other with the Lys residue that 20-atom A ZD maleimide joint shown in Figure 29 is modified via side chain in this peptide.

Figure 33 has shown the light chain of an embodiment of humanization 38c2 IgG1 and the aminoacid sequence of heavy chain.

Figure 34 has shown the subcutaneous transformation period (SC T1/2) and the biological effectiveness per-cent of compound of the present invention of the peptide of one of SEQ ID of the present invention of comprising according to following: K11:SEQ IDNO:29, K12:SEQ ID NO:5, K13:SEQ ID NO:28, K14:SEQ ID NO:27, K16:SEQ ID NO:26, K17:SEQ ID NO:25, K19:SEQ ID NO:24, K20:SEQ ID NO:23, K21:SEQ ID NO:22, K23:SEQ ID NO:21, K24:SEQ ID NO:20, K26:SEQ ID NO:19, K27:SEQ ID NO:132, K28:SEQ ID NO:18, K38:SEQ ID NO:14, C:SEQ ID NO:3, C1-30:SEQ ID NO:30, K21 1-33:SEQ ID NO:31, described compound by lysine residue or K (SH) residue (shown in the position, for example, K11 is meant by connecting at the 11st K or K (SH) residue) link to each other with h38c2 antibody via the joint of Fig. 1～Fig. 4.SC T1/2 (subcutaneous transformation period) obtains by compound S C is expelled in the mouse and by ELISA detection compound concentration.The SC biological effectiveness is represented from the compound curve below area of the mouse of IV injection and the ratio of the area of the same compound curve below of the mouse of injecting from SC.

Figure 35 has shown the result of glucose tolerance test (GTT).Single 0.3mg/kg SC dosage---the compound of the present invention that is used for Figure 35 is known as via Fig. 1～joint design and humanization zymohexase antibody h38c2 link coupled specificity SEQ ID NO shown in Figure 4:.As mentioned above with 0.3mg/kg SC with compound administration (still linking to each other) by replacing at the K of separately amino acid position or K (SH).A: from the merging of the test in 48 hours and the data of testing in 72 hours.The B:48 hour data.The C:72 hour data.

Figure 36 A～D food intake every day: shown to testing the result that the body weight change of identical animal is analyzed with Figure 35.

Figure 37 A～D: the accumulation body weight change of testing identical animal with Figure 35.

Figure 38 a and Figure 38 b have shown respectively according to embodiment of formula I with according to an embodiment of formula II or formula III.

Figure 39 a and Figure 39 b have shown respectively according to embodiment of formula I with according to an embodiment of formula II or formula III.

Figure 40 a and Figure 40 b have shown respectively according to embodiment of formula I with according to an embodiment of formula II or formula III.

Figure 41 a and Figure 41 b have shown respectively according to embodiment of formula I with according to an embodiment of formula II or formula III.

Figure 42 a and Figure 42 b have shown respectively according to embodiment of formula I with according to an embodiment of formula II or formula III.

Figure 43 a and Figure 43 b have shown respectively according to embodiment of formula I with according to an embodiment of formula II or formula III.

Figure 44 a and Figure 44 b have shown respectively according to embodiment of formula I with according to an embodiment of formula II or formula III.

Embodiment

Definition

Following abbreviation used herein, term and phrase are defined as follows.

The abbreviation of amino acid single-letter abbreviation trigram

2-aminoisobutyric acid--Aib2 or Aib

L-Ala A Ala

Arginine R Arg

L-asparagine N Asn

Aspartic acid D Asp

Halfcystine C Cys

L-glutamic acid E Glu

Glutamine Q Gln

Glycine G Gly

Histidine H His

Isoleucine I Ile

Leucine L Leu

Methionin K Lys

Methionine(Met) M Met

Nor-leucine--Nle

Ornithine--Orn

Phenylalanine F Phe

Proline(Pro) P Pro

Serine S Ser

Threonine T Thr

Tryptophane W Trp

Tyrosine Y Tyr

Xie Ansuan V Val

Unless indicate that by " D " prefix (for example, D-Ala or N-Me-D-Ile) stereochemistry of the alpha-carbon of amino acid in the peptide as herein described or aminoacyl residue is native configurations or " L " configuration in addition.Cahn-Ingold-Prelog " R " and " S " indicate the stereochemistry that the N that is used to indicate peptide holds the chiral centre of some acyl substituent." R, S " indicates the racemic mixture that is used for showing two kinds of corresponding isomeric form.R.S.Cahn is followed in this name, etc., Angew.Chem.Int.Ed.Engl. is described in the 5:385-415 (1966).

D-H is meant the D-Histidine.

2-aminoisobutyric acid used herein has following structure:

" polypeptide ", " peptide " and " albumen " are used in reference to the polymkeric substance for amino-acid residue interchangeably.As used herein, it is aminoacid polymers corresponding to naturally occurring amino acid whose artificial chemical analog that these terms can be applied to one of them above amino-acid residue.These terms also are applied to naturally occurring aminoacid polymers.Amino acid can be L type or D type, as long as kept the combined function of peptide.Peptide can be an annular, has in the peptide intramolecular bond between two non-adjacent amino acid, for example, and main chain and backbone cyclized, side chain and backbone cyclized and side chain and side chain cyclisation.Cyclic peptide can prepare by method well known in the art.For example see United States Patent (USP) the 6th, 013, No. 625; S.Cheng etc., J Med.Chem.37:1-8 (1994).

All peptide sequences are all write according to generally accepted pact, thus α-N terminal amino acid residue in the left side and α-C terminal amino acid residue on the right side.As used herein, term " N end " is meant the amino acid whose free alpha-amino group in the peptide, and term " C end " is meant the amino acid whose free carboxylic acid end in the peptide.Carry out the end capped peptide of N-with a group and be meant the peptide that on the alpha-amino nitrogen of N terminal amino acid residue, has group.Carry out the end capped amino acid of N-with a group and be meant the amino acid that on alpha-amino nitrogen, has group.

Usually, " replacement " is meant as the group of giving a definition, and the Cheng Jian of wherein contained one or more and hydrogen atom is substituted with the key that becomes of non-hydrogen or non-carbon atom, described non-hydrogen or non-carbon atom such as, but not limited to: such as halogen atoms such as F, Cl, Br and I; Such as the Sauerstoffatom in the groups such as hydroxyl, alkoxyl group, aryloxy and ester group; Such as the sulphur atom in the groups such as sulfydryl, alkylthio, arylthio, sulfuryl, alkylsulfonyl and sulfoxide group; Such as the nitrogen-atoms in the groups such as amido, amide group, alkylamino, dialkyl amido, arylamino, alkyl aryl amino, ammonia diaryl base, N-oxygen base, imide and enamine base; Such as the Siliciumatom in the groups such as trialkylsilkl, di alkylaryl silyl, alkyl diaryl silyl and diarye silyl; And other heteroatoms in various other groups.Substituted alkyl, substituted cycloalkyl are substituted group with other and comprise that also wherein one or more are become key alternate group with the Cheng Jian of carbon atom or hydrogen atom with heteroatomic, the oxygen in described heteroatoms such as carbonyl, carboxyl and the ester group or such as the nitrogen in the groups such as imido grpup, oximido, diazanyl and itrile group.As used herein, " optional replacement " group can be substituted or not be substituted.Therefore, for example " the optional alkyl that replaces " both referred to that substituted alkyl also referred to not substituted alkyl.

Phrase " not substituted alkyl " is meant and does not contain heteroatomic alkyl.Therefore, this phrase comprises straight chained alkyl, such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl or the like.This phrase also comprises the branched chain isomer of straight chained alkyl, includes but not limited to following example :-CH (CH ₃) ₂,-CH (CH ₃) (CH ₂CH ₃) ,-CH (CH ₂CH ₃) ₂,-C (CH ₃) ₃,-C (CH ₂CH ₃) ₃,-CH ₂CH (CH ₃) ₂,-CH ₂CH (CH ₃) (CH ₂CH ₃) ,-CH ₂CH (CH ₂CH ₃) ₂,-CH ₂C (CH ₃) ₃,-CH ₂C (CH ₂CH ₃) ₃,-CH (CH ₃) CH (CH ₃) (CH ₂CH ₃) ,-CH ₂CH ₂CH (CH ₃) ₂,-CH ₂CH ₂CH (CH ₃) (CH ₂CH ₃) ,-CH ₂CH ₂CH (CH ₂CH ₃) ₂,-CH ₂CH ₂C (CH ₃) ₃,-CH ₂CH ₂C (CH ₂CH ₃) ₃,-CH (CH ₃) CH ₂CH (CH ₃) ₂,-CH (CH ₃) CH (CH ₃) CH (CH ₃) ₂,-CH (CH ₂CH ₃) CH (CH ₃) CH (CH ₃) (CH ₂CH ₃) etc.This phrase does not comprise cycloalkyl.Therefore, phrase not substituted alkyl comprise primary alkyl, secondary alkyl and tertiary alkyl.Not substituted alkyl can with one or more carbon atoms, Sauerstoffatom, nitrogen-atoms and/or the sulfur atom linkage in the parent compound.Possible not substituted alkyl comprises straight chained alkyl and the branched-chain alkyl with 1～20 carbon atom.Alternatively, these substituted alkyl low alkyl groups of having 1～10 carbon atom or having 1～about 6 carbon atoms not.Other not substituted alkyl comprise straight chained alkyl with 1～3 carbon atom and branched-chain alkyl and comprise methyl, ethyl, propyl group and-CH (CH ₃) ₂

Phrase " substituted alkyl " be meant wherein one or more with the Cheng Jian of carbon or hydrogen by with non-hydrogen or non-carbon atom become not substituted alkyl of key alternate, described non-hydrogen or non-carbon atom such as, but not limited to: such as the halogen atom in the halogenide such as F, Cl, Br and I; Such as the Sauerstoffatom in the groups such as hydroxyl, alkoxyl group, aryloxy and ester group; Such as the sulphur atom in the groups such as sulfydryl, alkylthio, arylthio, sulfuryl, alkylsulfonyl and sulfoxide group; Such as the nitrogen-atoms in the groups such as amido, amide group, alkylamino, dialkyl amido, arylamino, alkyl aryl amino, ammonia diaryl base, N-oxygen base, imide and enamine base; Such as the Siliciumatom in the groups such as trialkylsilkl, di alkylaryl silyl, alkyl diaryl silyl and diarye silyl; And other heteroatoms in various other groups.Substituted alkyl comprises that also wherein one or more are become key alternate group with the Cheng Jian of carbon atom or hydrogen atom with heteroatomic, the oxygen in described heteroatoms such as carbonyl, carboxyl and the ester group or such as the nitrogen in the groups such as imido grpup, oximido, diazanyl and itrile group.Substituted alkyl comprises that in addition wherein one or more are become key alternate group with the Cheng Jian of carbon atom or hydrogen atom by one or more and fluorine atom.An example of substituted alkyl is that trifluoromethyl contains the alkyl of trifluoromethyl with other.Other alkyl comprises that thereby wherein one or more are substituted the group that this substituted alkyl contains hydroxyl, alkoxyl group, aryloxy or heterocyclic oxy group with the Cheng Jian of carbon atom or hydrogen atom with the key that becomes of Sauerstoffatom.Also have other alkyl to comprise and have amido, alkylamino, dialkyl amido, arylamino, (alkyl) (aryl) amino, ammonia diaryl base, heterocyclic radical amino, (alkyl) (heterocyclic radical) are amino, the alkyl of (aryl) (heterocyclic radical) amino or two heterocyclic radical amino.

Phrase " unsubstituting alkylidene " is meant the substituted alkyl not as herein defined of divalence.Therefore, methylene radical, ethylidene and the propylidene example of unsubstituting alkylidene of respectively doing for oneself.Phrase " substituted alkylene " is meant the substituted alkyl as herein defined of divalence.Replacement or unsubstituted low-grade alkylidene have 1～about 6 carbon atoms.

Phrase " unsubstituted ring alkyl " is meant such as cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl groups, and this class ring that replaces with straight chain defined herein and branched-chain alkyl.This phrase also comprises such as, but not limited to adamantyl norbornene, two multi-ring alkyls such as ring [2.2.2] octyl groups etc., and this class ring that replaces with straight chain defined herein and branched-chain alkyl.Therefore, this phrase will comprise methylcyclohexyl in addition.This phrase does not comprise and contains heteroatomic cycloalkyl.The unsubstituted ring alkyl can with one or more carbon atoms, Sauerstoffatom, nitrogen-atoms and/or the sulfur atom linkage in the parent compound.In some embodiments, the unsubstituted ring alkyl has 3～20 carbon atoms.In other embodiments, this class unsubstituted ring alkyl has 3～8 carbon atoms, and this class group has 3～7 carbon atoms in other embodiments.

Phrase " substituted cycloalkyl " with respect to the unsubstituted ring alkyl have with " substituted alkyl " with respect to the identical meaning of substituted alkyl not.Therefore, this phrase includes but not limited to oxo cyclohexyl, chloro cyclohexyl, hydroxy-cyclohexyl and chloromethyl cyclohexyl.

Phrase " unsubstituting aromatic yl " is meant and does not contain heteroatomic any aryl.Therefore, this phrase includes but not limited to such as groups such as phenyl, xenyl, anthryl and naphthyls.Although phrase " unsubstituting aromatic yl " comprises the group that contains such as condensed ring such as naphthalenes, but it does not comprise having such as the aryl with other group of one of the member who encircles bonding such as alkyl or halogeno-group, because will think substituted aryl as described below such as aryl such as tolyls herein.Usually, unsubstituting aromatic yl can be the lower aryl with 6～about 10 carbon atoms.A unsubstituting aromatic yl is a phenyl.Unsubstituting aromatic yl can with one or more carbon atoms, Sauerstoffatom, nitrogen-atoms and/or the sulfur atom linkage in the parent compound.

Phrase " substituted aryl " with respect to unsubstituting aromatic yl have with " substituted alkyl " with respect to the identical meaning of substituted alkyl not.Yet, substituted aryl also comprises the aryl of one of them aromatic carbon and non-carbon as herein described or non-hydrogen atom bonding, also comprises the aryl of one or more aromatic carbons of aryl wherein and replacement defined herein and/or unsubstituted alkyl, alkenyl or alkynyl bonding.These two atomic linkages that comprised two carbon atoms of aryl wherein and alkyl, alkenyl or alkynyl are to determine the bonding setting of condensed ring system (for example, dihydro naphthyl or tetralyl).Therefore, phrase " substituted aryl " includes but not limited to tolyl and hydroxy phenyl or the like.

Phrase " unsubstituting ene yl " is meant such as being relevant to described those straight chains of not substituted alkyl defined herein and side chain and cyclic group, but wherein has the two keys between two carbon atoms at least.Example include but not limited to vinyl ,-CH=C (H) (CH ₃) ,-CH=C (CH ₃) ₂,-C (CH ₃)=C (H) ₂,-C (CH ₃)=C (H) (CH ₃) ,-C (CH ₂CH ₃)=CH ₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl or the like.Rudimentary unsubstituting ene yl has 1～about 6 carbon atoms.

Phrase " substituted alkenyl " with respect to unsubstituting ene yl have with " substituted alkyl " with respect to the identical meaning of substituted alkyl not.Substituted alkenyl comprises wherein with thiazolinyl and one of them the non-carbon or the non-hydrogen atom of the carbon of another carbon atom Cheng Shuanjian and non-carbon or non-hydrogen atom bonding and has neither part nor lot in thiazolinyl with the carbon atom bonding of two keys of another carbon.For example ,-CH=CH-OCH ₃With-CH=CH-CH ₂-OH is a substituted alkenyl.Such as-CH=CH-C (O)-CH ₃Deng carbonyl substituted wherein CH ₂The oxo thiazolinyl of group also is a substituted alkenyl.

Phrase " does not replace alkenylene " and is meant the unsubstituting ene yl as herein defined of divalence.Therefore ,-CH=CH-is an example that does not replace alkenylene.Phrase " replacement alkenylene " is meant the substituted alkenyl as herein defined of divalence.

Phrase " unsubstituting polysulfide yl " is meant such as being relevant to described those straight chains of not substituted alkyl defined herein and side chain and cyclic group, but wherein has a triple bond between two carbon atoms at least.Example includes but not limited to-C ≡ C (H) ,-C ≡ C (CH ₃) ,-C ≡ C (CH ₂CH ₃) ,-C (H ₂) C ≡ C (H) ,-C (H) ₂C ≡ C (CH ₃) and-C (H) ₂C ≡ C (CH ₂CH ₃) or the like.Unsubstituted low-grade alkynyl has 1～about 6 carbon.

Phrase " substituted alkynyl " with respect to unsubstituting polysulfide yl have with " substituted alkyl " with respect to the identical meaning of substituted alkyl not.Substituted alkynyl comprises alkynyl and wherein non-carbon or the non-hydrogen atom that wherein becomes triple-linked carbon and non-carbon or non-hydrogen atom bonding with another carbon atom and has neither part nor lot in alkynyl with the triple-linked carbon atom bonding of another carbon.Example has included but not limited to wherein carbonyl substituted CH ₂The oxo alkynyl of group, such as-C (O)-CH ≡ CH-CH ₃With-C (O)-CH ₂-CH ≡ CH or the like.

Phrase " does not replace alkynylene " and is meant the unsubstituting polysulfide yl as herein defined of divalence.Therefore ,-C ≡ C-is an example that does not replace alkynylene.Phrase " replacement alkynylene " is meant the substituted alkynyl as herein defined of divalence.

Phrase " unsubstituting aromatic alkyl " is meant as herein defined not substituted alkyl, wherein this not the hydrogen bond of substituted alkyl or carbon bond by being substituted with the key that becomes of aryl defined herein.For example, methyl (CH ₃) be substituted alkyl not.If the hydrogen atom of methyl is substituted with the key that becomes of phenyl, if such as the bond with carbon of the carbon and the benzene of methyl, then this compound is unsubstituting aromatic alkyl (that is a benzyl).Therefore, this phrase includes but not limited to such as benzyl, diphenyl methyl and 1-phenylethyl (CH (C ₆H ₅) (CH ₃)) etc. group.

Phrase " substituted aralkyl " with respect to unsubstituting aromatic alkyl have with " substituted alkyl " with respect to the identical meaning of substituted alkyl not.Yet, substituted aralkyl also comprise the carbon bond of the moieties of this group wherein or hydrogen bond by with non-carbon or non-hydrogen atom become key institute alternate group.The example of substituted aralkyl includes but not limited to-CH ₂C (=O) (C ₆H ₅) and-CH ₂(2-aminomethyl phenyl) or the like.

Phrase " does not replace arylalkenyl " and is meant unsubstituting ene yl as herein defined, and wherein the hydrogen bond of this unsubstituting ene yl or carbon bond are substituted with the key that becomes of aryl defined herein.For example, vinyl is a unsubstituting ene yl.If the hydrogen atom of vinyl is substituted with the key that becomes of phenyl, if such as the bond with carbon of the carbon and the benzene of vinyl, then this compound is not replace arylalkenyl (that is styryl).Therefore, this phrase includes but not limited to such as styryl, diphenylacetylene and 1-phenyl vinyl (C (C ₆H ₅) (CH ₂)) etc. group.

Phrase " replacement arylalkenyl " with respect to do not replace arylalkenyl have with " substituted alkyl " with respect to the identical meaning of substituted alkyl not.Yet, replace arylalkenyl also comprise the carbon bond of the alkenyl part of this group wherein or hydrogen bond by with non-carbon or non-hydrogen atom become key alternate group.The example that replaces arylalkenyl includes but not limited to-CH=C (Cl) (C ₆H ₅) and-CH=CH (2-aminomethyl phenyl) or the like.

Phrase " does not replace sweet-smelling alkynyl " and is meant unsubstituting polysulfide yl as herein defined, and wherein the hydrogen bond of this unsubstituting polysulfide yl or carbon bond are substituted with the key that becomes of aryl as herein defined.For example, ethynyl is a unsubstituting polysulfide yl.If the hydrogen atom of ethynyl is substituted with the key that becomes of phenyl, if such as the bond with carbon of the carbon and the benzene of ethynyl, then this compound is not replace sweet-smelling alkynyl.Therefore, this phrase include but not limited to such as-C ≡ C-phenyl and-CH ₂Groups such as-C ≡ C-phenyl.

Phrase " replacement sweet-smelling alkynyl " with respect to do not replace sweet-smelling alkynyl have with " substituted alkyl " with respect to the identical meaning of substituted alkyl not.Yet, replace arylalkenyl also comprise the carbon bond of the alkynyl part of this group wherein or hydrogen bond by with non-carbon or non-hydrogen atom become key alternate group.The example that replaces sweet-smelling alkynyl includes but not limited to-C ≡ C-C (Br) (C ₆H ₅) and-C ≡ C (2-aminomethyl phenyl) or the like.

Phrase " replaces assorted alkyl " and is meant as herein defined not substituted alkyl, and wherein carbochain is selected from one or more heteroatomss interruptions of N, O and S.The assorted alkyl of not replacement that contains N can have NH or N (not substituted alkyl) in carbochain.Therefore, do not replace assorted alkyl and comprise alkoxyl group, alkoxyalkyl, alkoxyl group alkoxyl group, thioether group, alkylamino alkyl, aminoalkoxy and other this class group.Usually, do not replace assorted alkyl and contain 1～5 heteroatoms, particularly 1～3 heteroatoms.In some embodiments, do not replace assorted alkyl and for example comprise, such as alkoxyl group alkoxyl group alkoxyl groups such as ethoxy ethoxy ethoxies.

Phrase " replace assorted alkyl " with respect to do not replace assorted alkyl have with " substituted alkyl " with respect to the identical meaning of substituted alkyl not.

What phrase " replace assorted alkylidene group " was meant divalence replaces assorted alkyl as herein defined.Therefore ,-CH ₂-O-CH ₂-and-CH ₂-NH-CH ₂CH ₂-all be the example that does not replace assorted alkylidene group.Phrase " the assorted alkylidene group of replacement " is meant the assorted alkyl of replacement as herein defined of divalence.

Phrase " replaces assorted thiazolinyl " and is meant unsubstituting ene yl as herein defined, and wherein carbochain is selected from one or more heteroatomss interruptions of N, O and S.The assorted thiazolinyl of not replacement that contains N can have NH or N (not substituted alkyl or thiazolinyl) in carbochain.Phrase " replace assorted thiazolinyl " with respect to do not replace assorted thiazolinyl have with " replacing assorted alkyl " with respect to not replacing the identical meaning of alkyl of mixing.

What phrase " replace assorted alkenylene " was meant divalence replaces assorted thiazolinyl as herein defined.Therefore ,-CH ₂-O-CH=CH-is an example that does not replace assorted alkenylene.Phrase " the assorted alkenylene of replacement " is meant the assorted thiazolinyl of replacement as herein defined of divalence.

Phrase " replaces assorted alkynyl " and is meant unsubstituting polysulfide yl as herein defined, and wherein carbochain is selected from one or more heteroatomss interruptions of N, O and S.The assorted alkynyl of not replacement that contains N can have NH or N (not substituted alkyl, unsubstituting ene yl or alkynyl) in carbochain.Phrase " replace assorted alkynyl " with respect to do not replace assorted alkynyl have with " replacing assorted alkyl " with respect to not replacing the identical meaning of alkyl of mixing.

What phrase " replace assorted alkynylene " was meant divalence replaces assorted alkynyl as herein defined.Therefore ,-CH ₂-O-CH ₂-C ≡ C-is an example that does not replace assorted alkynylene.Phrase " the assorted alkynylene of replacement " is meant the assorted alkynyl of replacement as herein defined of divalence.

Phrase " unsubstituting heterocycle yl " is meant aromatic cycle compound and non-aromatic ring compound, comprise contain the ring members more than three monocycle, dicyclo and polycyclic cyclic cpds (for example, quinuclidine base quinuclidyl), having in described ring members more than one is such as, but not limited to heteroatomss such as N, O and S.Although phrase " unsubstituting heterocycle yl " comprises such as fused heterocycles such as benzimidazolyl-s, but it does not comprise having such as the heterocyclic radical with other group of one of ring members bonding such as alkyl or halogeno-group, because be the heterocyclic radical that replaces such as compounds such as 2-tolimidazole bases.The example of heterocyclic radical includes but not limited to: the unsaturated triatomic ring～octatomic ring that contains 1～4 nitrogen-atoms, such as, but not limited to pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridine base, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (for example, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazyl (for example, 1H-tetrazyl, 2H-tetrazyl etc.); Saturated triatomic ring～the octatomic ring that contains 1～4 nitrogen-atoms is such as, but not limited to pyrrolidyl, imidazolidyl, piperidyl, piperazinyl; The unsaturated assorted condensed ring radical that contains 1～4 nitrogen-atoms is such as, but not limited to indyl, pseudoindoyl, indoline base, indolyl, indolizine base, benzimidazolyl-, quinolyl, isoquinolyl, indazolyl, benzotriazole base; Unsaturated triatomic ring～the octatomic ring that contains 1～3 Sauerstoffatom and 1～3 nitrogen-atoms, Zhu as but Bu Xian Yu oxazolyl, isoxazolyl, oxadiazole base (for example, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, 1,2,5-oxadiazole base etc.); Saturated triatomic ring～the octatomic ring that contains 1～2 Sauerstoffatom and 1～3 nitrogen-atoms is such as, but not limited to morpholinyl; The unsaturated assorted condensed ring radical that contains 1～2 Sauerstoffatom and 1～3 nitrogen-atoms, for example, benzoxazolyl, Ben Bing oxadiazole base, benzoxazinyl (for example, 2H-1,4-benzoxazinyl etc.); Unsaturated triatomic ring～the octatomic ring that contains 1～3 sulphur atom and 1～3 nitrogen-atoms is such as, but not limited to thiazolyl, isothiazolyl, thiadiazolyl group (for example, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group etc.); Saturated triatomic ring～the octatomic ring that contains 1～2 sulphur atom and 1～3 nitrogen-atoms is such as, but not limited to thiazolidyl (thiazolodinyl); Saturated and the unsaturated triatomic ring～octatomic ring that contains 1～2 sulphur atom is such as, but not limited to thienyl, dihydro dithia cyclohexadienyl (dihydrodithiinyl), dihydro dithia cyclohexanedione base (dihydrodithionyl), tetrahydro-thienyl, tetrahydro thiapyran base; The unsaturated assorted condensed ring radical that contains 1～2 sulphur atom and 1～3 nitrogen-atoms, such as, but not limited to benzothiazolyl, diazosulfide base, benzothiazine base (for example, 2H-1,4-benzothiazine base etc.), dihydrobenzo thiazinyl (for example, 2H-3,4-dihydrobenzo thiazinyl etc.); Unsaturated triatomic ring～the octatomic ring that contains Sauerstoffatom is such as, but not limited to furyl; The unsaturated assorted condensed ring radical that contains 1～3 Sauerstoffatom is such as benzo dioxolyl (for example, 1,3-benzo dioxolyl etc.); Unsaturated triatomic ring～the octatomic ring that contains Sauerstoffatom and 1～2 sulphur atom is such as, but not limited to dihydro oxathiene base (dihydrooxathiinyl); Saturated triatomic ring～the octatomic ring that contains 1～3 Sauerstoffatom and 1～2 sulphur atom, such as 1,4-oxathiane base; The unsaturated condensed ring that contains 1～2 sulphur atom is such as benzothienyl, benzo dithia cyclohexenyl (benzodithiinyl); And the unsaturated assorted condensed ring radical that contains a Sauerstoffatom and 1～3 sulphur atom, such as benzo oxygen dithia cyclohexenyl (benzoxathiinyl).Heterocyclic radical also comprises wherein an above S atom in the ring and above-mentioned those groups (sulfoxide and sulfone) of one or two Sauerstoffatom Cheng Shuanjian.For example, heterocyclic radical comprises tetramethylene sulfide, oxidation tetramethylene sulfide and 1,1-titanium dioxide tetramethylene sulfide.In some embodiments, heterocyclic radical contains 5 or 6 ring memberses.In other embodiments, heterocyclic radical comprises morpholine, piperazine, piperidines, tetramethyleneimine, imidazoles, pyrazoles, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, thiomorpholine, wherein the S atom of thiomorpholine and thiomorpholine, pyrroles, high piperazine, oxazolidine-2-ketone, pyrrolidin-2-one, oxazole, rubane, thiazole, isoxazole, furans and the tetrahydrofuran (THF) of more than one O atomic linkage.

Phrase " substituted heterocyclic radical " is meant the unsubstituting heterocycle yl as herein defined of one of them ring members and non-hydrogen atom bonding, such as with respect to substituted alkyl and substituted aryl as mentioned above.Example includes but not limited to 2-tolimidazole base, 5-tolimidazole base, 5-chloro benzothiazole base, 1-methylpiperazine base and 2-chloropyridine base or the like.

Phrase " not substituted heteroaryl " is meant unsubstituted fragrant heterocyclic radical as herein defined.Therefore, substituted heteroaryl does not include but not limited to furyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, benzimidazolyl-and benzothiazolyl.Phrase " substituted heteroaryl " is meant the fragrant heterocyclic radical as herein defined of replacement.

Phrase " unsubstituting heterocycle yl alkyl " is meant as herein defined not substituted alkyl, wherein this hydrogen bond of substituted alkyl or carbon bond are not substituted with the key that becomes of heterocyclic radical as herein defined.For example, methyl (CH ₃) be substituted alkyl not.If the hydrogen atom of methyl is substituted with the key that becomes of heterocyclic radical, if such as the carbon of methyl and the carbon 2 of pyridine (with one of carbon of the N bonding of pyridine) bonding or with the carbon 3 or carbon 4 bondings of pyridine, then this compound is the unsubstituting heterocycle yl alkyl.

Phrase " substituted heterocyclic radical alkyl " has the meaning identical with respect to unsubstituting aromatic alkyl with " substituted aralkyl " with respect to the unsubstituting heterocycle yl alkyl.Yet the substituted heterocyclic radical alkyl also comprises the group of heteroatoms (such as, but not limited to the piperidines ring nitrogen of the piperidyl alkyl) bonding in the heterocycle of wherein non-hydrogen atom and this heterocyclic radical alkyl.

Phrase " unsubstituting heterocycle yl thiazolinyl " is meant unsubstituting ene yl as herein defined, and wherein the hydrogen bond of this unsubstituting ene yl or carbon bond are substituted with the key that becomes of heterocyclic radical as herein defined.For example, vinyl is a unsubstituting ene yl.If the hydrogen atom of vinyl is substituted with the key that becomes of heterocyclic radical, if such as carbon 2 bondings of the carbon of vinyl and pyridine or with the carbon 3 or carbon 4 bondings of pyridine, then this compound is the unsubstituting heterocycle yl thiazolinyl.

Phrase " substituted heterocyclic radical thiazolinyl " with respect to the unsubstituting heterocycle yl thiazolinyl have with " replacement arylalkenyl " with respect to not replacing the identical meaning of arylalkenyl.Yet the substituted heterocyclic radical thiazolinyl also comprises the group of heteroatoms (such as, but not limited to the piperidines ring nitrogen of the piperidyl thiazolinyl) bonding in the heterocycle of wherein non-hydrogen atom and this heterocyclic radical thiazolinyl.

Phrase " unsubstituting heterocycle yl alkynyl " is meant unsubstituting polysulfide yl as herein defined, and wherein the hydrogen bond of this unsubstituting polysulfide yl or carbon bond are substituted with the key that becomes of heterocyclic radical as herein defined.For example, ethynyl is a unsubstituting polysulfide yl.If the hydrogen atom of ethynyl is substituted with the key that becomes of heterocyclic radical, if such as carbon 2 bondings of the carbon of ethynyl and pyridine or with the carbon 3 or carbon 4 bondings of pyridine, then this compound is the unsubstituting heterocycle yl alkynyl.

Phrase " substituted heterocyclic radical alkynyl " with respect to the unsubstituting heterocycle yl alkynyl have with " replacement sweet-smelling alkynyl " with respect to not replacing the identical meaning of sweet-smelling alkynyl.Yet the substituted heterocyclic radical alkynyl also comprises the group of heteroatoms (such as, but not limited to the piperidines ring nitrogen of the piperidyl alkynyl) bonding in the heterocycle of wherein non-hydrogen atom and this heterocyclic radical alkynyl.

Phrase " unsubstituting alkoxy " is meant that wherein (OH), described alkyl is a not substituted alkyl defined herein by the key institute alternate hydroxyl that becomes with the carbon atom of alkyl with the Cheng Jian of hydrogen atom when not carrying out that described one-tenth key substitutes.

Phrase " substituted alkoxy " is meant that wherein (OH), described alkyl is a substituted alkyl defined herein by the key institute alternate hydroxyl that becomes with the carbon atom of alkyl with the Cheng Jian of hydrogen atom when not carrying out that described one-tenth key substitutes.

" pharmacologically acceptable salt " comprises and mineral alkali, organic bases, mineral acid, organic acid or alkalescence or salt that acidic amino acid became.The salt of mineral alkali comprises, for example, and such as basic metal such as sodium or potassium; Such as alkaline-earth metal or aluminium such as calcium and magnesium; And ammonia.The salt of organic bases comprises, for example Trimethylamine 99, triethylamine, pyridine, picoline, thanomin, diethanolamine and trolamine.The salt of mineral acid comprises, for example hydrochloric acid, hydrogen borate (hydroboric acid), nitric acid, sulfuric acid and phosphoric acid.Organic acid salt comprises, for example formic acid, acetate, trifluoroacetic acid, fumaric acid, oxalic acid, tartrate, toxilic acid, citric acid, succsinic acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid and tosic acid.The salt of basic aminoacids comprises, for example arginine, Methionin and ornithine.Acidic amino acid comprises, for example aspartic acid and L-glutamic acid.

" tautomer " is meant the isomeric form of the compound in the balance that is in each other.The concentration of isomeric form depends on the environment of finding compound and may be solid or in the organic solution or the aqueous solution and different according to for example compound.For example, in the aqueous solution, ketone usually and its enol form be in balance.Therefore, ketone and enol thereof are called tautomer each other.One of ordinary skill in the art will readily recognize that various functional groups and other structure may show tautomerism, and have formula I, II and III compound all tautomers all within the scope of the invention.

Can be with compound solvation, especially aquation of the present invention.Aquation can occur in described compound or comprise during the manufacturing of this compound compositions, or owing to the hygroscopic nature of this compound can carry out taking place along with the time.

Some embodiment is the derivative that is called prodrug.Statement " prodrug " is meant the derivative of pharmacologic activity medicine or therapeutic activity medicine, for example ester and acid amides, and wherein this derivative is compared with former medicine and has been strengthened transport property and therapeutic value and be converted into medicine by enzymic process or chemical process.For example see R.E.Notari, Methods Enzymol.112:309-323 (1985); N.Bodor, Drugs of the Future 6:165-182 (1981); H.Bundgaard, and Chapter 1 in Design of Prodrugs (H.Bundgaard, ed.), Elsevier, New York (1985); With A.G.Gilman etc., Goodman And Gilman ' s The PharmacologicalBasis of Therapeutics, 8th ed., McGraw-Hill (1990).Therefore, prodrug design can be changed medicine metabolic stability or conveying characteristic, shielding Side effects of pharmaceutical drugs or toxicity, improve taste of medicine or change other characteristic or the character of medicine.

Compound of the present invention comprises the optical isomer at any or all asymmetric atom place enrichment or that split, and is apparent in as shown.Thereby racemic mixture can be separated with diastereo-isomerism mixture and individual optical isomer or synthetic its corresponding isomer or the non-corresponding isomer of not containing substantially.All these steric isomers all within the scope of the invention.

Term used herein " carboxyl-protecting group " is meant the carboxylic acid protectiveness ester group that is used for blocking or protecting carboxylic functionality when the reaction of other functional site that relates to compound is carried out.Carboxyl-protecting group is disclosed in for example Greene, Protective Groups in Organic Synthesis, pp.152-186, John Wiley﹠amp; Sons, among the New York (1981), this paper is introduced into by reference.In addition, carboxyl-protecting group can be used as prodrug, thereby can by for example enzymic hydrolysis this carboxyl-protecting group be cut easily to discharge its biological activity parent in vivo.T.Higuchi and V.Stella exist " Pro-drugs as Novel Delivery Systems ", Vol.14, A.C.S.Symposium Series provides the thorough discussion to the prodrug notion among the American Chemical Society (1975), this paper is introduced into by reference.These carboxyl-protecting groups are known for those skilled in the art; and in penicillin and cynnematin field, be widely used in protecting carboxyl; as United States Patent (USP) the 3rd; 840,556 and 3,719; No. 667, S.Kukolja; J.Am.Chem.Soc.93:6267-6269 (1971) and G.E.Gutowski, described in the Tetrahedron Lett.21:1779-1782 (1970), this paper introduces its disclosure by reference.The example of ester class that can be used as the prodrug of carboxylic compound can be at for example BioreversibleCarriers in Drug Design:Theory and Application (E.B.Roche, ed.), Pergamon Press, find in the 14th～21 page among the New York (1987), this paper is introduced into by reference.Representative carboxyl-protecting group is C ₁～C ₈Alkyl (for example, methyl, ethyl or tertiary butyl or the like); Haloalkyl; Thiazolinyl; Cycloalkyl and substitutive derivative thereof are such as cyclohexyl, cyclopentyl or the like; Cycloalkylalkyl and substitutive derivative thereof are such as cyclohexyl methyl, cyclopentyl-methyl or the like; Aralkyl, for example, styroyl or benzyl and such as substitutive derivatives such as alkoxybenzyl or nitrobenzyls; Arylalkenyl, for example, styryl or the like; Aryl and substitutive derivative thereof, for example, 5-indanyl or the like; Dialkyl aminoalkyl (for example, dimethyl aminoethyl or the like); Alkanol oxygen base is such as acetoxy-methyl, butyryl acyloxy methyl, valeryl oxygen ylmethyl (valeryloxymethyl), isobutyl acyl-oxygen ylmethyl, isoamyl acyl-oxygen ylmethyl (isovaleryloxymethyl), 1-(propionyloxy)-1-ethyl, 1-(pivaloyl oxygen base)-1-ethyl, 1-methyl isophthalic acid-(propionyloxy)-1-ethyl, pivaloyl oxygen ylmethyl, propionyloxy methyl or the like; Cycloalkanol oxygen base alkyl is such as cyclopropyl carbonyl oxygen ylmethyl, cyclobutyl carbonyl oxygen ylmethyl, cyclopentylcarbonyl oxygen ylmethyl, cyclohexyl-carbonyl oxygen ylmethyl or the like; The aryl acyloxy alkyl is such as benzoyloxy methyl, benzoyloxy ethyl or the like; Aromatic alkyl carbonyl oxygen base alkyl is such as benzyloxycarbonyl group oxygen ylmethyl, 2-benzyloxycarbonyl group oxygen base ethyl or the like; Alkoxy carbonyl alkyl is such as methoxycarbonyl methyl, cyclohexyloxy carbonyl methyl, 1-methoxycarbonyl-1-ethyl or the like; The alkoxy-carbonyl oxy alkyl is such as methoxycarbonyl oxygen ylmethyl, tert-butoxycarbonyl oxygen ylmethyl, 1-ethoxy carbonyl Oxy-1-ethyl, 1-cyclohexyloxy carbonyl Oxy-1-ethyl or the like; The alkoxycarbonyl amino alkyl is such as tert-butoxycarbonyl amino methyl or the like; The alkyl amino-carbonyl aminoalkyl group is such as methylamino carbonylamino methyl or the like; The alkanol aminoalkyl group is such as acetylamino methyl or the like; Heterocyclic radical ketonic oxygen base alkyl, such as, 4-methylpiperazine base ketonic oxygen ylmethyl or the like; The dialkyl amino carbonyl alkyl is such as dimethylamino carbonyl methyl, diethylamino carbonyl methyl or the like; (5-(alkyl)-2-oxo-1, the alkyl of 3-dioxy cyclopentenes-4-yl) is such as (the 5-tertiary butyl-2-oxo-1,3-dioxy cyclopentenes-4-yl) methyl or the like; And (5-phenyl-2-oxo-1,3-dioxy cyclopentenes-4-yl) alkyl, such as (5-phenyl-2-oxo-1,3-dioxy cyclopentenes-4-yl) methyl or the like.

Term used herein " N protecting group " or " N protection " are meant and are used at the N of building-up process protection amino acid or peptide end or amino those groups that are not subjected to undesirable reaction of protection.N protecting group commonly used is disclosed in for example Greene, Protective Groups in OrganicSynthesis, John Wiley﹠amp; Among Sons, the New York (1981), this paper is introduced into by reference.The N protecting group comprises acyl group, such as formyl radical, ethanoyl, propionyl, pivaloyl group, tertiary butyl ethanoyl, 2-chloracetyl, 2-acetyl bromide, trifluoroacetyl group, tribromo-acetyl base, phthaloyl, ortho-nitrophenyl oxygen base ethanoyl, α-chlorobutyryl, benzoyl, 4-chlorobenzene formacyl, 4-benzoyl bromide, 4-nitro benzoyl or the like; Alkylsulfonyl is such as benzenesulfonyl, p-toluenesulfonyl or the like; Form the group of carbamate, such as benzyloxycarbonyl, to the chlorine benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, to the nitro benzyloxycarbonyl, 2-nitro benzyloxycarbonyl, to the bromo-benzyloxy-carbonyl, 3,4-dimethoxy benzyloxycarbonyl, 3,5-dimethoxy benzyloxycarbonyl, 2,4-dimethoxy benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro-4,5-dimethoxy benzyloxycarbonyl, 3,4,5-trimethoxy benzyloxycarbonyl, 1-(to xenyl)-1-methyl ethoxy carbonyl, α, alpha-alpha-dimethyl-3,5-dimethoxy benzyloxycarbonyl, benzhydryloxycarbonyl, tert-butoxycarbonyl, the di-isopropyl methoxycarbonyl, isopropoxy carbonyl, ethoxy carbonyl, methoxycarbonyl, allyloxy carbonyl, 2,2,2 ,-trichlorine ethoxy carbonyl, phenyloxycarbonyl, the 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, the cyclopentyloxy carbonyl, the Buddha's warrior attendant alkoxy carbonyl, cyclohexyloxy carbonyl, the thiophenyl carbonyl obtains; Alkyl is such as benzyl, trityl group, benzyloxymethyl or the like; And silyl, such as trimethyl silyl or the like.In some embodiments, the N protecting group is formyl radical, ethanoyl, benzoyl, pivaloyl group, tertiary butyl ethanoyl, benzenesulfonyl, benzyl, 9-fluorenyl methoxy carbonyl (Fmoc), tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

As used herein, " halo ", " halogen " or " halogenide " are meant F, Cl, Br or I.

As used herein; unless otherwise noted; to abbreviation and their usage, generally acknowledged abbreviation or the IUPAC-IUB Commission onBiochemical Nomenclature of any protecting group, amino acid or other compound, Biochem.11:942-944 (1972) is consistent.

As used herein, " substantially pure " is meant evenly basic so that do not present the impurity that can detect easily by the standard method of analysis (such as thin-layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) etc.) that is used for estimating purity by those skilled in the art, to such an extent as to or the enough pure physical properties and the chemical property that can not change material that be further purified with detecting, such as enzymic activity and biological activity etc.Being used for purifying compounds is well known by persons skilled in the art with the method that produces the purified compound of basic chemistry.Yet chemical substantially purified compound can be the mixture of steric isomer.In this case, be further purified the activity specific that can increase this compound.

As used herein, " biological activity " is meant compound, composition or other mixture or the activity in vivo of the physiologic response that causes when administered compound, composition or other mixture in vivo.Therefore biological activity has contained the result of treatment and the pharmaceutical activity of these compounds, composition and mixture.

As used herein, " pharmacokinetics " is meant along with the time carries out being applied compound concentrations in serum.Pharmacodynamics is meant along with the time is applied the concentration of compound in target and non-target tissue and the effect (toxicity) on effect on the target tissue (curative effect) and non-target tissue.Can be by designing the improvement on for example pharmacokinetics or pharmacodynamics for particular target such as the chemical property (changing solubleness, electric charge etc.) of using labile bond or changing any joint to agent or biological agent.

As used herein, phrase " significant quantity " and " treatment significant quantity " are meant the dosage that is enough to be provided at the sufficiently high concentration of giving beneficial effect (for example, the improvement of symptom) on its receptor.Concrete treatment effective dose level for any specific study subject will depend on various factors, these factors comprise activity, route of administration, this compound of seriousness, the particular compound of the illness of being treated, illness clearance rate, treatment time length, with this compound combination or overlap age, body weight, sex, diet and the general health situation of medicine, study subject of use and medical field and medical science in known similar factor.Determining that the various generality of being considered in " treatment significant quantity " are considered is well known by persons skilled in the art and at for example Gilman, A.G., Deng, Goodman And Gilman ' s The Pharmacological Basis ofTherapeutics, 8th ed., McGraw-Hill (1990); And Remington ' sPharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, PA is illustrated in (1990).

On the one hand, the invention provides the covalently bound various target compounds of wherein GA target agent and antibody combining site.

On the other hand, the invention provides at least one physical property of change GA target agent or the method for biological nature.Described method comprises the agent of GA target is direct or next covalently bound with antibody combining site by joint.Characteristic that can the agent of adorned GA target includes but not limited to binding affinity, to the susceptibility of degraded (for example, pass through proteolytic enzyme), the adjusting of pharmacokinetics, pharmacodynamics, immunogenicity, solubleness, lipotropy, wetting ability, hydrophobicity, stability (more stable or more unstable, and planned degraded), rigidity, flexibility, antibodies or the like.In addition, the effector function that provides by adding antibody can increase the biological value of specific GA target agent.For example, a kind of antibody provides such as complementary and has been mediated effector function.Do not wish to be subjected to any theory constraint, the antibody moiety of GA target compound can prolong the GA target agent transformation period in vivo of smaller szie usually.Therefore, on the one hand, the invention provides the method for the effective circulating half-life that is used to increase the agent of GA target.

On the other hand, the invention provides be used for regulating by the agent of GA target is linked to each other with the antibody combining site covalency antibody in conjunction with active method.Although do not wish to be subjected to any theory constraint, antibody and the remarkable reduction of antigenic combination may spatially hinder antigen by the GA target agent that is connected and contact with antibody combining site and cause.Substituting is, if the amino acid side chain of the antibody combining site of being modified by covalent linkage then may cause the antigen bonded significantly to reduce for combining very importantly with antigenic.On the contrary, when the GA target agent that is connected spatially do not hinder contacting of antigen and antibody combining site and/or when the amino acid side chain of the antibody combining site of being modified by covalent linkage for combining when inessential with antigenic, may cause antibody to increase with antigenic the combination significantly.

On the other hand, the present invention includes the modified antibodies binding site to produce method to the binding specificity of GLP-1R.This method comprises the chemical part on the joint of the reactive amino of antibody combining site acid side chain and GA target agent-linker compounds as described herein covalently bound, and wherein this GA target agent is special to GLP-1R.Thereby the chemical part of described joint from the agent of GA target enough far away when GA target agent-linker compounds is covalently bound with antibody combining site the agent of GA target can combine with GLP-1R.In one embodiment, covalently bound preceding antibody will have less than about 1 * 10 ^-5The avidity to GLP-1R of mol.Yet after this antibody and GA target agent-linker compounds were covalently bound, the antibody after the modification preferably had at least about 1 * 10 ^-6The avidity to target molecules of mol, substituting is at least about 1 * 10 ^-7Mol, substituting is at least about 1 * 10 ^-8Mol, substituting is at least about 1 * 10 ^-9Mol, or substituting be at least about 1 * 10 ^-10Mol.

The agent of GA target

In one embodiment, the agent of GA target is:

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-R ²(SEQ IDNO：1)，

Wherein:

SEQ ID NO:1 is 30 the amino acid whose GLP-1 (7-36) that GLP-1 produced the 2nd L-Ala place cutting by DPP IV (DPP-IV).D.J.Drucker.Endocrinology?142：521-527(2001)。GLP-1 (7-36) serves as the GLP-1R agonist, thereby causes the increase of the insulin secretion of glucose dependence.Yet the transformation period of GLP-1 (7-36) only is several minutes.

In another embodiment, the agent of GA target is:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：2)；

Wherein

SEQ ID NO:2 is 39 amino acid whose peptides (exendin-4, incretin analogues-4).The insulin secretion similar to GLP-1 (7-36), that exendin-4 serves as the GLP-1R agonist and stimulates glucose to rely on.Yet different with GLP-1 (7-36) is that exendin-4 has tolerance to the cutting of DPP-IV.The N petiolarea of GLP-1 (7-36) and exendin-4 much at one, significant difference is second amino-acid residue.This residue is a L-Ala in GLP-1 (7-36), but is glycine in exendin-4.This single amino acid is the reason of exendin-4 to DPP-IV digestion tolerance.Between exendin-4 and the GLP-1 (7-36) another significantly difference is to have nine additional amino acid residues at the C of exendin-4 end place, and these additional amino acid residues have formed the tryptophane cage.

Except the peptide of SEQ ID NO:1 or SEQ ID NO:2, GA target disclosed herein agent can be the analogue of these sequences.These analogues may be used for extra favourable characteristics, such as, the host immunity identification of glucose tolerance, islet cells test reaction and/or the reduction of for example appetite of the treating diabetes overview of the stability of the biological effectiveness of Zeng Jiaing, increase, improvement, improvement control, the weight management of improving, improvement.As used herein, the analogue of the peptide of SEQ IDNO:1 or SEQ ID NO:2 is the sequence that has SEQ ID NO:1 or SEQID NO:2 substantially, but has one or more aminoacid replacement, insertion or disappearance or their combination.

In some embodiments, the GA target agent that this paper provided comprises SEQ ID NO:1 or SEQ ID NO:2, but has one or more aminoacid replacement.The aminoacid replacement that a class in the agent of GA target is possible will comprise that those amino acid that are predicted to be the structure that can stablize SEQ ID NO:1 or SEQ IDNO:2 change.Utilize SEQ ID NO:1 or SEQ ID NO:2, those skilled in the art can easily write out consensus sequence, and determine to represent the conservative amino acid residues of preferred amino acids replacement from these consensus sequences.Aminoacid replacement can be conservative property or non-conservation.The conservative amino acid residue replaces and comprises the one or more amino acid that substitute SEQ ID NO:1 or SEQ ID NO:2 with the amino acid of similar electric charge, size and/or hydrophobic characteristics, such as, for example L-glutamic acid (E) is to the aminoacid replacement of aspartic acid (D).The non-conservation aminoacid replacement comprises the one or more amino acid that substitute SEQ ID NO:1 or SEQ ID NO:2 with the amino acid that has dissimilar electric charge, size and/or hydrophobic characteristics, such as, for example L-glutamic acid (E) is to the replacement of Xie Ansuan (V).In some embodiments, the GA target agent that this paper provided comprises SEQ ID NO:1 or SEQ ID NO:2 analogue, but the glycine residue on having replaced the 2nd with 2-aminoisobutyric acid (Aib2) (or L-Ala, depend on the circumstances).In some embodiments, the GA target agent that this paper provided comprises SEQ ID NO:1 or SEQID NO:2, but has the one or more residues that replace with Methionin.

In some embodiments, the GA target agent that this paper provided comprises SEQ ID NO:1 or SEQ ID NO:2, but has one or more aminoacid insertion.Aminoacid insertion can comprise single amino acids residue or residue section.Insertion can be carried out at the carboxy terminal place of peptide or the interior location place of peptide.The length range of such insertion is generally 2～10 amino acid.Be contemplated that the insertion of carrying out at the carboxyl terminal place of peptide may have wideer size range, may be about 2～about 20 amino acid.Can in SEQ ID NO:1 or SEQ ID NO:2, introduce one or more such insertions, as long as such insertion produces the peptide that still shows the GLP-1R agonist activity.

In some embodiments, the GA target peptide that this paper provided comprises the aminoacid sequence of SEQ ID NO:2, but has the lysine residue of one or more insertions.For example, in one embodiment, the agent of GA target is:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：3)；

Wherein

Except added an extra lysine residue at carboxyl terminal, the GA target agent of SEQ ID NO:3 is identical with SEQ ID NO:2.

In a similar embodiment, the agent of GA target is:

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?IDNO：33)；

Wherein:

Except added an extra lysine residue at carboxyl terminal, the GA target agent of SEQ ID NO:33 is identical with SEQ ID NO:1.

In some embodiments, the GA target agent that this paper provided comprises SEQ ID NO:1 or SEQ ID NO:2, but has one or more aminoacid deletion.Such disappearance can comprise from the brachymemma of the carboxyl terminal of peptide, or they can comprise remove one or more amino acid from the interior location of peptide.Such disappearance may relate to the combination of consecutive miss or the some disappearance and the consecutive miss of single-point disappearance, plural continuous residue.Can in SEQ ID NO:1 or SEQID NO:2, introduce one or more such disappearances, as long as such disappearance produces the peptide that still shows the GLP-1R agonist activity.In some embodiments, the GA target peptide that this paper provided comprises the aminoacid sequence of SEQ ID NO:2, but the carboxy terminal deletion of one or more amino acid from peptide arranged.

Suitable exemplary SEQ ID NO:1 and SEQ ID NO:2 analogue are described in down in the Table I, and describe with the general formula form in this article.Peptide sequence in the Table I is listed to carboxyl terminal (right side) from aminoterminal (left side).

Table I

SEQ ID NO:1 and SEQ ID NO:2 analogue

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：3)

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：4)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：5)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGG-R ²(SEQ?ID?NO：6)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKN-R ²(SEQ?ID?NO：7)

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKN-R ²(SEQ?ID?NO：8)

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKN-R ²(SEQ?ID?NO：9)

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：10)

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：11)

R ¹-HAibEGTFTSDLSK(Ac)QMEEEAVRLFIEWLK(Ac)NGGPSSGAPPPS-R ²(SEQ?ID?NO：12)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPKS-R ²(SEQ?ID?NO：14)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAKPPS-R ²(SEQ?ID?NO：15)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSKAPPPS-R ²(SEQ?ID?NO：16)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPKSGAPPPS-R ²(SEQ?ID?NO：17)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKKGGPSSGAPPPS-R ²(SEQ?ID?NO：18)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWKKNGGPSSGAPPPS-R ²(SEQ?ID?NO：19)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIKWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：20)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFKEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：21)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)

R ¹-HAibEGTFTSDLSKQMEEEAVKLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)

R ¹-HAibEGTFTSDLSKQMEEEAKRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)

R ¹-HAibEGTFTSDLSKQMEEKAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：25)

R ¹-HAibEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)

R ¹-HAibEGTFTSDLSKQMEKEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)

R ¹-HAibEGTFTSDLSKQKEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)

R ¹-HAibEGTFTSDLSKKMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：28)

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)

R ¹-HAibEGTFTSDLKKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：29)

R ¹-HAibEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)

R ¹-HAibEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK-R ²(SEQ?ID?NO：30)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK(SH)-R ²(SEQ?ID?NO：114)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSS-R ²(SEQ?ID?NO：31)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGR-R ²(SEQ?ID?NO：32)

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：33)

R ¹-HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：34)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：35)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibRK-R ²(SEQ?ID?NO：36)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：37)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)

R ¹-HAibEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)

R ¹-HAibEGTFTSDVSSYGEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：40)

R ¹-HAibEGTFTSDVSSYCEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：41)

R ¹-HAibEGTFTSDVSSYFEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：42)

R ¹-HAibEGTFTSDVSSYYEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：43)

R ¹-HAibEGTFTSDVSSYWEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：44)

R ¹-HAibEGTFTSDVSSYLEEQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：45)

R ¹-HAibEGTFTSDVSSYLEDQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：46)

R ¹-HAibEGTFTSDVSSYLEKQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：47)

R ¹-HAibEGTFTSDVSSYLEGQAVKEFIAWLVKAibR-R ²(SEQ?ID?NO：48)

R ¹-HAibEGTFTSDVSSYLEGQAIKEFIAWLVKAibR-R ²(SEQ?ID?NO：49)

R ¹-HAibEGTFTSDVSSYLEGQALKEFIAWLVKAibR-R ²(SEQ?ID?NO：50)

R ¹-HAibEGTFTSDVSSYLEGQAAREFIAWLVKAibR-R ²(SEQ?ID?NO：51)

R ¹-HAibEGTFTSDVSSYLEGQAAOrnEFIAWLVKAibR-R ²(SEQ?ID?NO：52)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAFLVKAibR-R ²(SEQ?ID?NO：53)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLIKAibR-R ²(SEQ?ID?NO：54)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVRAibR-R ²(SEQ?ID?NO：55)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVOrnAibR-R ²(SEQ?ID?NO：56)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：57)

R ¹-HAibEGTFTSDVSSYFEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：58)

R ¹-HAibEGTFTSDVSSYYEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：59)

R ¹-HAibEGTFTSDVSSYWEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：60)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIRAibR-R ²(SEQ?ID?NO：61)

R ¹-HAibEGTFTSDVSSYLEEQAVREFIAWLIRAibR-R ²(SEQ?ID?NO：62)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：63)

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：171)

R ¹-HAibEGTFTSDKSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：64)

R ¹-HAibEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：116)

R ¹-HAibEGTFTSDVSKYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：65)

R ¹-HAibEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：117)

R ¹-HAibEGTFTSDVSSYKEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：66)

R ¹-HAibEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：118)

R ¹-HAibEGTFTSDVSSYLEKQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：67)

R ¹-HAibEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：119)

R ¹-HAibEGTFTSDVSSYLEEQKVKEFIAWLIKAibR-R ²(SEQ?ID?NO：68)

R ¹-HAibEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAibR-R ²(SEQ?ID?NO：120)

R ¹-HAibEGTFTSDVSSYLEEQAVKEKIAWLIKAibR-R ²(SEQ?ID?NO：69)

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAibR-R ²(SEQ?ID?NO：121)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIKWLIKAibR-R ²(SEQ?ID?NO：70)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIK(SH)WLIKAibR-R ²(SEQ?ID?NO：122)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWKIKAibR-R ²(SEQ?ID?NO：71)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWK(SH)IKAibR-R ²(SEQ?ID?NO：123)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK-R ²(SEQ?ID?NO：72)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：124)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK(Ac)AibR-R ²(SEQ?ID?NO：73)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK (benzoyl) AibR-R ²(SEQ ID NO:74)

K used herein (SH) is meant:

K used herein (benzoyl) is meant the lysine residue that links to each other with the benzoyl end-blocking with following structure:

" anti--the 3-caproyl " used herein is meant the end-blocking that links to each other and have following structure with GA target peptide:

" 3-aminophenyl ethanoyl " used herein is meant the end-blocking that links to each other and have following structure with GA target peptide:

Can use techniques well known to prepare the GA target compound.Usually, the synthetic of peptidyl GA target agent is the first step, and as described herein carrying out.Then with this target agent be connected component (joint) and connect and to carry out derivatize, then merge with antibody.The person skilled in the art will easily understand that used concrete synthesis step depends on the definite character of three components.Therefore, can easily synthesize GA target agent as herein described-joint conjugate and GA target compound.

Can synthesize GA target agent peptide by many technology well known by persons skilled in the art.Synthetic for solid-phase polypeptide, to the summary of many technology can Chemical Approaches tothe Synthesis of Peptides and Proteins (Williams etc., eds.), CRC Press, Boca Raton, FL finds in (1997).

Usually, the GA target agent peptide of expecting according to the continuous solid phase synthesis of approach well known.For example see No. the 10/205th, 924, U.S. Patent application (disclosing 2003/0045477A1 number).Can be with joint on solid phase top or append on the peptide fully, or can add (seeing Fig. 5 A and Fig. 5 B) with solution phase technology in that peptide is being removed the back from resin.For example, can append to such as 4-methylol-phenoxymethyl-poly-resins such as (vinylbenzene-1% Vinylstyrenes) containing the amino of N protection and the connection portion of carboxylic acid.Can remove the N protecting group with suitable acid (for example, TFA is used for Boc) or alkali (for example, piperidines is used for Fmoc), the normal C of Chan Shenging holds to the peptide sequence (seeing Fig. 5 A) of N end form then.Substituting is, can synthesize peptide sequence earlier and then joint be added on post in the peptide and (see Fig. 5 B).Also have another kind of method between synthesis phase, to carry out derivatize with suitable side chain deprotection and with the active joint of appropriate reaction.For example, can react with the lysine residue deprotection and with joint with active ester groups.Substituting is, the alpha-amino nitrogen under amino acid derivative or some situation can be added the part as the peptide sequence in the growth, and described amino acid derivative has the shank that appends to the due care on the side chain.

When solid phase synthesis finishes, successively or in a single operation target agent-joint conjugate is removed and deprotection from resin.Can by with cutting reagent (for example, contain such as scavenging agents such as thioanisole (thioanisole), water or dithioglycols trifluoroacetic acid) to handling in a single operation, to finish removing and deprotection of target agent-joint conjugate with the peptide-joint conjugate of resin-bonded.Behind the deprotection and release of target agent, can carry out the further derivatize of target agent peptide.

By a series of chromatographic steps the target agent-joint conjugate of complete deprotection is carried out purifying, described chromatographic step adopts any or all following type: the ion-exchange on the weakly base resin of acetate form; Hydrophobic adsorption chromatography on the polystyrene-divinylbenzene (for example, AMBERLITE XAD) of underivatized; Silica gel adsorption chromatography; Ion-exchange chromatography on carboxymethyl cellulose; Distribution chromatography, for example, on SEPHADEX G-25, LH-20 or adverse current distribute; High performance liquid chromatography (HPLC), the especially reversed-phase HPLC on octyl group silicon oxide or octadecyl silyl silicon oxide bonded chromatographic column condiment.

Antibody

" antibody " used herein comprises the product immunoglobulin (Ig) of B cell and the product TXi Baoshouti (TcR) and the varient thereof of varient and T cell thereof.Immunoglobulin (Ig) is the albumen that comprises substantially by one or more polypeptide of immunoglobulin (Ig) κ and λ, α, γ, δ, ζ and μ constant region gene and a large amount of immune globulin variable region gene codings.Light chain is divided into κ and λ.Heavy chain is divided into γ, μ, α, δ or ζ, and they have defined immunoglobulin (Ig) kind: IgG, IgM, IgA, IgD and IgE conversely respectively.The subclass of heavy chain also is known.For example, the IgG heavy chain can be any subclass of IgG1, IgG2, IgG3 and IgG4.

The immunoglobulin structure unit of known typical comprises the tetramer.To forming, and each polypeptide chain is to having " gently " chain (about 25kD) and " weight " chain (about 50kD～70kD) by two identical polypeptide chains for each tetramer.The N end of each bar chain has been determined main about amino acid whose variable region more than 100～110 of being responsible for antigen recognition.Variable light chain (the V of term _L) and variable heavy chain (V _H) refer to these light chains and heavy chain respectively.The amino acid of antibody can be for natural or non-natural.

The antibody that contains two heavy chains and two light chains is owing to having two binding sites thereby being divalence.Typical natural bivalent antibody is IgG.Antibody can be multivalence, as the dimeric forms of IgA and the situation of pentamer IgM molecule.Antibody also can be unit price, such as, the segmental situation of Fab or Fab ' for example.

Antibody exists or exists as the good fragment of a plurality of signs that the digestion by various peptases or chemical substance produces as the harmless antibody of total length.Therefore, for example, thereby stomach en-has produced the dimer F (ab ') of Fab at the disulfide linkage place of hinge area digestion antibody ₂, Fab self is by disulfide linkage and V _H-CH ₁The light chain that connects.Can under mild conditions, reduce F (ab ') ₂So that make the disulfide bonds in the hinge area, thereby with F (ab ') ₂Dimer is converted into Fab ' monomer.Fab ' monomer is that the Fab fragment that has the part hinge area (is for example seen Fundamental Immunology (W.E.Paul, ed.), Raven Press, N.Y. (1993)) for the more detailed description of other antibody fragment basically.Although various antibody fragments determine according to the digestion of harmless antibody, it is complete synthesis or by utilizing recombinant DNA method to synthesize to it will be understood by those skilled in the art that any various antibody fragment can carry out chemistry.Therefore, term antibody used herein also comprises the antibody fragment that produces by the modification to complete antibody, complete synthesis antibody fragment or the antibody fragment that is obtained by recombinant DNA method.The antibody fragment that produces by recombinant technology may comprise by proteolytic ferment to be processed known fragment or may be the unique fragment unavailable or unknown so far by proteolytic ferment processing.One skilled in the art will realize that and use the antibody fragment ratio to use complete antibody more favourable in some cases.For example, the size that antibody fragment is littler has allowed quick removing, and can cause the improvement that enters to solid tumor.

The heterodimer that the disulfide linkage that TXi Baoshouti (TcR) is made up of two chains connects.These two chains form disulfide linkage short the extension in the amino acid section near the T cytoplasmic membrane outside usually, and described amino acid section is similar to antibody hinge region.Each bar TcR chain is made up of an antibody sample variable region and a constant region.TcR has the molecular weight of about 95kD fully, and the size of individual chain does not wait from 35kD～47kD.In addition, the implication of TcR has also contained this receptor of part, such as, for example can use the variable region of approach well known as the soluble proteins generation.For example, United States Patent (USP) the 6th, 080, No. 840 and A.E.Slanetz and A.L.Bothwell, Eur.J.Immunol.21:179-183 (1991) is to the solvable TXi Baoshouti by the regional montage in the extracellular of TcR is prepared to the film anchor series of the glycosylation phosphatidylinositols (GPI) of Thy-1.This molecule is expressed in cell surface when not having CD3, and can come to cut from film by the processing of phosphatidylinositols specificity Phospholipid hydrolase (PI-PLC).Solvable TcR can also pass through TcR variable domain and heavy chain of antibody CH ₂Territory or CH ₃The territory is coupled and prepares, basic as United States Patent (USP) the 5th, 216, No. 132 and G.S.Basi etc., described in the J.Immunol.Methods 155:175-191 (1992), or prepare, as E.V.Shusta etc. as soluble TcR strand, Nat.Biotechnol.18:754-759 (2000) or P.D.Holler etc., Proc.Natl.Acad.Sci.U.S.A.97:5387-5392 (2000) is described.An embodiment of the invention use TcR " antibody " as soluble antibody.Can identical method is identified TcR by reference CDR district and other framework residue binding site be discussed by using with as above antagonist.

Recombinant antibodies can be conventional full length antibody, from the known antibody fragment of proteolytic enzyme digest, such as Fv or strand Fv antibody fragments such as (scFv), such as V _HOr V _LDeng single domain fragment, double-stranded antibody, territory disappearance antibody, miniantibody or the like.Fv antibody is of a size of about 50kD and comprises light chain and the variable region of heavy chain.Light chain and heavy chain can be expressed in respectively in the bacterium, they are assembled into the Fv fragment therein.Substituting is, can be with two chain through engineering approaches to form interchain disulfide bond to provide dsFv.Strand Fv (" scFv ") comprises by getting involved the V that joint sequence connects _HAnd V _LThe single polypeptide in sequence territory, thus the tertiary structure of gained has been simulated the structure of antibody combining site when this polypeptide is folding.See J.S.Huston etc., Proc.Nat.Acad.Sci.U.S.A.85:5879-5883 (1988).Single domain antibody is the minimum functional combining unit (the about 13kD of size) of antibody, corresponding to heavy V _HChain or light V _LThe variable region of chain.See United States Patent (USP) the 6th, 696, No. 245, WO04/058821, WO04/003019 and WO03/002609.Single domain antibody is expressed in bacterium, yeast and other lower eukaryotes expression system well.Territory disappearance antibody has lacked such as territories such as CH2 with respect to full length antibody.In many cases these territories disappearance antibody particularly CH2 disappearance antibody provide the removing that improves with respect to their counterpart.Similar to full length antibody, double-stranded antibody is divalence.Contain during miniantibody and directly link to each other with CH3 or via getting involved the V that the IgG hinge links to each other _H, V _LOr the fusion rotein of scFv.See T.Olafsen etc., Protein Eng.Des.Sel.17:315-323 (2004).Similar to territory disappearance antibody,, miniantibody has the removing of improvement thereby having been kept the binding specificity of full length antibody by through engineering approaches owing to its littler molecular weight.

Develop various technology and be used to produce antibody fragment.Traditionally, these fragments produce via the proteolytic enzyme digest of harmless antibody and (for example see K.Morimoto and K.Inouye, J.Biochem.Biophys.Methods 24:107-117 (1992); M.Brennan etc., Science229:81-83 (1985)).Yet, can directly produce these fragments by the reorganization host cell now.Fab, Fv and scFv antibody fragment can both be expressed in the intestinal bacteria and be come out from secretion wherein, thereby make and can produce these a large amount of fragments easily.Can from antibody phage discussed above storehouse, isolate antibody fragment.Substituting is to form F (ab ') thereby can directly reclaim Fab '-SH fragment from intestinal bacteria and carry out chemical coupling ₂Fragment (P.Carter etc., Biotechnology 10:163-167 (1992)).According to another kind of method, can from reorganization host cell culture, directly isolate F (ab ') ₂Fragment.At United States Patent (USP) the 5th, 869, in No. 046 to comprising Fab and the F (ab ') that remedies acceptor in conjunction with the transformation period in the body that has increase of epi-position ₂Fragment is illustrated.Other technology that is used to produce antibody fragment will it will be apparent to those skilled in the art.

Binding site is meant and participates in antigen bonded antibody molecule part.Antibody combining site is formed by the amino-acid residue of the N end variable region (" V ") of heavy chain (" H ") and light chain (" L ").Antibody variable region comprises and is called " hypervariable region (hypervariable region) " and " complementary determining region " three height diversity fragments (CDR), and these height diversity fragments are between being called between " framework region " more conservative flanking fragment (FR).In antibody molecule, three hypervariable regions (LCDR1, LCDR2 and LCDR3) of light chain and three hypervariable regions (HCDR1, HCDR2 and HCDR3) of heavy chain thus in three-dimensional space, relative to each other arrange and formed antigen mating surface or antigen binding pocket.Therefore, antibody combining site has been represented the amino acid of the CDR that constitutes antibody and any framework residue of formation binding site pocket.

Can use approach well known to determine the identity of the amino-acid residue in the specific antibodies of formation binding site.For example, antibody CDR can be accredited as initial hypervariable region by definition such as Kabat.See E.A.Kabat etc., Sequences of Proteins of ImmunologicalInterest, 5th ed., Public Health Service, NIH, Washington D.C. (1992).The position of CDR can also be accredited as initial structural ring structure by explanations such as Chothia.For example see C.Chothia﹠amp; A.M.Lesk, J.Mol.Biol.196:901-917 (1987); C.Chothia etc., Nature 342:877-883 (1989); With A.Tramontano etc., J.Mol.Biol.215:175-182 (1990).Other method comprises " AbM definition " (trading off between Kabat and the Chothia, use the AbM antibody simulation software (present Accelrys) of Oxford Molecular to derive from), or R.M.MacCallum etc., " the contact definition (contact definition) " described in the J.Mol.Biol.262:732-745 (1996).Following table is identified CDR based on various known definition:

CDR Kabat AbM Chothia contacts (Contact)

L1 L24-L34 L24-L34 L24-L34 L30-L36

L2 L50-L56 L50-L56 L50-L56 L46-L55

L3 L89-L97 L89-L97 L89-L97 L89-L96

H1 (Kabat numbering) H31-H35B H26-H35B H26-H32..H34 H30-H35B

H1 (Chothia numbering) H31-H35 H26-H35 H26-H32 H30-H35

H2 H50-H56 H50-H58 H52-H56 H47-H58

H3 H95-H102 H95-H102 H95-H102 H93-H101

The general policy of CDR from Sequence Identification antibody is as follows separately:

LCDR1：

Initial---about No. 24 residues.

Residue Cys always before.

Residue Trp always continues with Tyr-Gln usually, but also continues with Leu-Gln, Phe-Gln or Tyr-Leu afterwards.

Length is 10～17 residues.

LCDR2：

Initial---L1 finishes back 16 residues.

Sequence Ile-Tyr normally before, but also can be Val-Tyr, Ile-Lys or Ile-Phe.

Length is generally 7 residues.

LCDR3：

Initial---L2 finishes back 33 residues.

Residue is Cys before.

Sequence is Phe-Gly-X-Gly afterwards.

Length is 7～11 residues.

HCDR1：

Initial---about No. 26 residues, 4 residues behind the Cys under the Chothia/AbM definition; Initial behind 5 residues under Kabat definition.

Sequence is Cys-X-X-X before.

Residue is Trp afterwards, continues with Val usually, but also continues with Ile or Ala.

Length is 10～12 residues under the AbM definition; Last 4 residues are got rid of in the Chothia definition.

HCDR2：

Initial---the CDR-H1 of Kabat/AbM definition finishes back 15 residues.

Sequence Leu-Glu-Trp-Ile-Gly normally before, but have some variations.

Sequence is Lys/Arg-Leu/Ile/Val/Phe/Thr/Ala-Thr/Ser/Ile/Ala afterwards.

Length is 16～19 residues under the Kabat definition; Last 7 residues are got rid of in the AbM definition.

HCDR3：

Initial---CDR-H2 finishes back 33 residues (latter two residue of Cys).

Sequence is Cys-X-X (normally Cys-Ala-Arg) before.

Sequence is Trp-Gly-X-Gly afterwards.

Length is 3～25 residues.

Yet can use the identity of determining to be in amino-acid residue in the specific antibodies of a part that but constitutes binding site outside the CDR such as approach well known such as molecular simulation and X-ray crystallographies, described amino-acid residue have the liner (lining) as binding site a part side chain (promptly can be used for connection) by binding site thus constitute the part of this binding site.For example see L.Riechmann etc., Nature 332:323-327 (1988).

As discussed above, can be used for preparing need be at the reactive side chain of antibody combining site based on the antibody of the GA target compound of antibody.Reactive side chain can natural existence or is placed antibody by sudden change.The reactive residue of antibody combining site may be relevant with antibody, and such as when described residue during by the nucleic acid encoding that is present in the lymphoidocyte, described nucleic acid is identified at first to make described antibody.Substituting is, thereby amino-acid residue can produce (for example seeing that WO 01/22922) by the specific residue of encoding of mutant DNA on purpose.Reactive residue can use the biosynthesizing of unique codon tRNA and aminoacyl tRNA discussed in this article in conjunction with the non-natural residue that produces for for example passing through.In another approach, amino-acid residue or its reactive functional groups (for example, nucleophilic amino or sulfydryl) can be appended on the amino-acid residue of antibody combining site.Therefore, the covalent linkage with antibody that " by the amino-acid residue of antibody combining site " used herein produces is meant directly or the Cheng Jian of the amino-acid residue by chemical part and antibody combining site that described chemical part links to each other with the side chain of the amino-acid residue of antibody combining site.

Catalytic antibody is a source that has the antibody of the binding site that comprises one or more reactive amino acid side chains.This antibody comprises zymohexase antibody, beta-lactam enzyme antibody, esterase antibody, Ntn hydrolase antibody or the like.

An embodiment comprises zymohexase antibody, such as mouse monoclonal antibody mAb 38C2 or mAb 33F12 and suitable humanization of this antibody-like and chimeric form.Mouse mAb 38C2 has close HCDR3 but at the reactive Methionin in its outside, and is the prototype by the new catalytic antibody of reactive immunity and the natural zymohexase generation of mechanism simulation.See C.F.Barbas3 ^RdDeng, Science 278:2085-2092 (1997)).Operable other zymohexase catalytic antibody comprises the antibody that is produced by following hybridoma: hybridoma 85A2, and the ATCC accession number is PTA-1015; Hybridoma 85C7, the ATCC accession number is PTA-1014; Hybridoma 92F9, the ATCC accession number is PTA-1017; Hybridoma 93F3, the ATCC accession number is PTA-823; Hybridoma 84G3, the ATCC accession number is PTA-824; Hybridoma 84G11, the ATCC accession number is PTA-1018; Hybridoma 84H9, the ATCC accession number is PTA-1019; Hybridoma 85H6, the ATCC accession number is PTA-825; Hybridoma 90G8, the ATCC accession number is PTA-1016.By reactive Methionin, these antibody use natural zymohexase the catalysis of enamine mechanism the reaction of aldol reaction and retrograde aldol condensation.For example see J.Wagner etc., Science 270:1797-1800 (1995); C.F.Barbas 3 ^RdDeng, Science 278:2085-2092 (1997); G.Zhong etc., Angew.Chem.Int.Ed.Engl.38:3738-3741 (1999); A.Karlstrom etc., Proc.Natl.Acad.Sci.U.S.A., 97:3878-3883 (2000).At United States Patent (USP) the 6th, 210,938,6,368,839,6,326,176,6,589,766,5,985,626 and 5,733, disclose zymohexase antibody in No. 757 and produced the method for zymohexase antibody.

Can also by with the agent of GA target with become key to form the GA target compound such as those reactive halfcystines of in the binding site of thioesterase catalytic antibody and esterase catalyzed antibody, finding.K.D.Janda etc., Proc.Natl.Acad.Sci.U.S.A.91:2532-2536 (1994) is illustrated suitable thioesterase catalytic antibody.P.Wirsching etc., Science270:1775-1782 (1995) is illustrated suitable esterase antibody.Can prepare the antibody that contains reactive amino acid by approach well known, described method comprises the antibody combining site residue suddenlyd change carries out chemical derivatization with the encoding reaction acidic amino acid or with the amino acid side chain of the joint antagonist binding site that contains reactive group.

The antibody of Shi Yonging can be by the immunity of routine immunization, body internal reaction or by such as selecting to obtain with the reactivity in vitro of phage display in this article.Can in people or other animal species, produce antibody.Antibody modification from an animal species can be reflected another animal species.For example, people's chimeric antibody is the antibody of at least one district of wherein antibody from human normal immunoglobulin.Usually be appreciated that people's chimeric antibody has from the non-human animal's of for example rodents variable region and from people's constant region.On the contrary, humanized antibody use from non-human antibody's CDR and great majority or all variable framework region and all constant regions all from human normal immunoglobulin.Can prepare chimeric antibody and humanized antibody by approach well known, described method comprises that CDR grafting method (for example sees N.Hardman etc., Int.J.Cancer44:424-433 (1989); C.Queen etc., Proc.Natl.Acad.Sci.U.S.A.86:10029-10033 (1989)), chain reorganization strategy (is for example seen, Rader etc., Proc.Natl.Acad.Sci.U.S.A.95:8910-8915 (1998), molecular simulation strategy (are for example seen, M.A.Roguska etc., Proc.Natl.Acad.Sci.U.S.A.91:969-973 (1994)) or the like.

Be illustrated in the art being used for that the non-human antibody is carried out humanized method.Preferably, humanized antibody has from inhuman source and is incorporated into one or more amino acid.These non-human amino-acid residues are so-called " introducing " residue, described " introducing " residue takes from usually " introducing " variable domain.Basically people's such as Winter method be can follow and (P.T.Jones etc., Nature 321:522-525 (1986) for example seen; L.Riechmann etc., Nature 332:323-327 (1988); M.Verhoeyen etc., Science 239:1534-1536 (1988)) carry out humanization by the corresponding sequence that replaces human antibodies with the hypervariable region sequence.So, this " humanization " antibody is chimeric antibody (S.Cabilly etc., Proc.Natl.Acad.Sci.U.S.A.81:3273-3277 (1984)), wherein being less than a harmless human variable region is basically replaced by the corresponding sequence from the non-human species.In practice, humanized antibody normally wherein some hypervariable region residue and may some framework (FR) residue by the human antibodies that residue replaced in the similar site of rodents antibody.

When intention was used for people's therepic use with antibody, the selection that is ready to use in the human variable domain (light territory and heavy territory) of making humanized antibody was replied extremely important for reducing antigenicity and human anti-mouse antibody (HAMA).According to the method that is called " best-fit ", be used for humanized human variable domain and be selected from the known domain storehouse, described known domain storehouse based on high homology (M.J.Sims etc., J.Immunol., the 151:2296-2308 (1993) of interested rodents variable region; M.Chothia and A.M.Lesk, J.Mol.Biol.196:901-917 (1987)).Another kind method has been used the framework region of everyone the antibody-like consensus sequence that is derived from specific light chain or heavy chain subgroup.The identical frames district can be used for several different humanized antibodies and (for example see P.Carter etc., Proc.Natl.Acad.Sci.U.S.A.89:4285-4289 (1992); L.G.Presta etc., J.Immunol., 151:2623-2632 (1993)).

The height that has importantly kept in humanization the Z group at antibody connects avidity in addition.In order to reach this purpose,, analyze auxiliary sequence by the three-dimensional model that uses auxiliary sequence and humanization sequence and prepared humanized antibody with each ways makes conceptual researches humanization product according to a kind of method.Three-dimensional immunoglobulin (Ig) model normally those skilled in the art can utilize and be familiar with.The computer program that can utilize the possible three-dimensional conformation structure to candidate's immunoglobulin sequences of choosing to describe and show.To the inspection of these displayings make can analyze residue about with the function of the candidate's immunoglobulin sequences that is connected of Z group in may act on.So, thereby can and introduce sequence selection and merge the antibody characteristic that the FR residue reach expectation from receptor, such as increase to the antigenic avidity of target.

Various forms to humanization mouse zymohexase antibody thinks over.An embodiment has used and has had human constant region C _κAnd C _{γ 1}1 humanization zymohexase catalytic antibody h38c2IgG1 or h38c2Fab.C.Rader etc., J.Mol.Bio.332:889-899 (2003) discloses the gene order and the carrier that can be used for producing h38c2Fab and h38c2IgG1.The light chain of h38c2IgG1 and sequence of heavy chain are as shown in Figure 33.Fig. 6 has shown variable light chain and variable heavy chain (being respectively SEQ ID NO:79 and SEQ ID NO:80) and the human variable light chain of system and the sequence alignment between the variable heavy chain of planting of the variable light chain of m38c2 and variable heavy chain (being respectively SEQ ID NO:77 and SEQ ID NO:78), h38c2.The human kind is V _kGene DPK-9 (SEQ IDNO:81) and people J _kGene JK4 (SEQ ID NO:83) is used for the humanization in kappa light chain variable territory as framework, and human the kind is gene DP-47 (SEQ ID NO:82) and people J _HGene JH4 (SEQID NO:84) is used for the humanization of the heavy chain variable domain of m38c2 as framework.H38c2 also can use IgG2, IgG3 or IgG4 constant domain, comprises any its allotype (allotype).The embodiment of h38c2IgG1 has used Glm (f) allotype.Another embodiment has used the variable domain (V that comprises h38c2 _LAnd V _H) and from the chimeric antibody of the constant domain of IgG1, IgG2, IgG3 or IgG4.

Various forms to humanization zymohexase antibody fragment thinks in addition.Embodiment has used h38c2F (ab ') ₂H38c2F (ab ') ₂Can produce by the proteolytic enzyme digest of h38c2IgG1.Another embodiment has used the V that comprises from h38c2 _LAnd V _HThe h38c2scFv in territory, the V of described h38c2 _LAnd V _HThe territory can be randomly by getting involved joint (Gly ₄Ser) ₃Link to each other.

As humanized alternative method, can generate human antibodies.For example, can produce now and can when immunity (or the reactive immunity in the situation at catalytic antibody), not have the transgenic animal (for example, mouse) that produce full spectrum (full repertoire) human antibodies under the endogenous immunoglobulin product.For example, heavy chain of antibody joining region (J in the chimeric and racial immunity globulin gene array in the mutant mice that these kinds are has been described _H) the homozygosity disappearance of gene can cause and produce human antibodies when antigen stimulation.For example see A.Jakobovits etc., Proc.Natl.Acad.Sci.U.S.A.90:2551-2555 (1993); A.Jakobovits etc., Nature362:255-258 (1993); M.Bruggemann etc., Year Immunol.7:33-40 (1993); L.D.Taylor waits Nucleic Acids Res.20:6287-6295 (1992); M.Bruggemann etc., Proc.Natl.Acad.Sci.U.S.A.86:6709-6713 (1989)); With WO 97/17852.

Different with the chemical derivative of typical antibody, be derived from the antibody derivatives of immunity can be in its binding site at specific position by specific marker, thereby help fast and controllably to prepare the homogeneous product.In addition, different with the chemical derivative of antibody, be derived from 1, the antibody derivatives of the reactive immunity of 3-diketone is a reversible.Because this reversibility can discharge the derovatives with mAb 38C2 bonded GA target compound by the competition with covalent attachment haptens JW (see J.Wagner etc., Science 270:1797-1800 (1995)) or related compound from antibody.This make under the situation of untoward reaction in vivo can be at once in and conjugate.Substituting is, non-reversible covalent bonds is possible, such as with the covalent linkage of the beta-lactam derivative of zymohexase antibody and target compound.Different with typical antihapten antibody, covalency diketone bonded antibody has the covalent linkage that is formed between diketone and the antibody and is in advantage between pH 3～pH11.Be increased in prescription, transmission and the standing storage aspect of the antibody stability that links to each other with its target agent covalency provide extra advantage.

Substituting is, can use display technique of bacteriophage (for example to see, J.McCafferty etc., Nature 348:552-553 (1990)) use immunoglobulin variable (V) domain gene spectrum to come at external generation human antibodies and antibody fragment from non-immune donor.According to this technology, antibody V domain gene is met frame ground (in-frame) be cloned in the main capsid protein gene or less important capsid protein gene such as filobactiviruses such as M13 or fd, and be illustrated in as the functional antibodies fragment on the surface of this phage particle.Because the filobactivirus particle contains the single stranded DNA duplicate of phage genome, also caused the selection of the gene that the antibody that has represented these character is encoded based on the selection of the functional property of antibody.Therefore, this phage has been simulated some character of B cell.Phage display can carry out in various ways, and at for example K.S.Johnson and D.J.Chiswell, Curr.Opin.Struct.Biol.3:564-571 summarizes in (1993).Several sources of V gene fragment can be used for phage display.T.Clackson etc., Nature352:624-628 (1991) has isolated multiple anti-azolactone antibody array from the little combinatorial libraries at random of the V gene of the spleen that is derived from immune mouse.Can make up V gene profile from non-immune human donor, and can follow J.D.Marks etc. substantially, J.Mol.Biol.222:581-597 (1991) or A.D.Griffiths etc., EMBO J.12:725-734 (1993) described technology antibody of resisting multiple antigen array (comprising autoantigen) separate.Also see United States Patent (USP) the 5th, 565,332 and 5,573, No. 905; With L.S.Jespers etc., Biotechnology 12:899-903 (1994).

As above indicated, human antibodies also can be produced by external activated B cell.For example see United States Patent (USP) the 5th, 567,610 and 5,229,275; With C.A.K.Borrebaeck etc., Proc.Natl.Acad.Sci.U.S.A.85:3995-3999 (1988).

Amino acid sequence modifications to antibody as herein described thinks over.For example, may it is desirable to improve binding affinity and/or other biological property of antibody.The variant amino acid sequence body of antibody prepares by introducing suitable Nucleotide change in antibody nucleic acid or synthesizing by polypeptide.These modifications for example comprise, disappearance, insertion and/or the replacement of the residue in the aminoacid sequence of antagonist.Disappearance, insertion and the replacement that can carry out any combination arrive final construct, as long as final construct has desired characteristics.Process after the translation of amino acid variation also change antibody is such as number that has changed glycosylation site or position.

Be used to identify as the specific residue of the antibody of preferred sudden change position or the process useful in zone be called " L-Ala scanning sudden change ", as B.C.Cunningham﹠amp; J.A.Wells is described in the Science244:1081-1085 (1989).Herein, identified the residue of target residue or group (for example, such as charged residues such as Arg, Asp, His, Lys and Glu) and with its with neutral amino acids or electronegative amino acid (most preferably Ala or poly-L-Ala) thus substitute the interaction of the Z group that influences amino acid and joint.Then by further introducing mutant or introduce other mutant and come those amino acid positions that demonstrate the functional susceptibility that replaces are carried out refinement replacing site.Therefore, be used to introduce the site that aminoacid sequence changes although pre-determined, the character of sudden change itself does not need to pre-determine.For example,, carried out L-Ala scanning sudden change or random mutation, become the ability of covalent linkage to screen it with Z-shaped the antibody variation body of expressing then at target codon or target zone for the performance of the sudden change of analyzing given site.

Aminoacid sequence inserts and comprises that the aminoterminal of length range from a residue to the polypeptide that contains 100 above residues merges and/or carboxyl terminal merges, and inserts in the sequence of single or multiple amino-acid residues.The terminal example that inserts comprises antibody that has N end methionyl or the antibody that merges with the cytotoxicity polypeptide.The insertion varient of other antibody molecule comprises that the N of antibody holds or the syzygy of the polypeptide of the serum half-life of C end and enzyme or increase antibody.

Another kind of varient type is the aminoacid replacement varient.These varients have by at least one amino-acid residue in the different residue alternate antibody molecules.Comprise the hypervariable region for the most interested site of substituted sudden change, but also considered the FR change.Shown the conservative property sudden change in the following table of title for " the preferred replacement ".If these sudden changes have caused bioactive change, then can be introduced in the more substantial variation of by name " the exemplary replacement " that further specify below with reference to the amino acid type and product is screened.

Modify by selecting to replace the substance that has realized the antibody biological property, the described polypeptide backbone structure that is substituted in its maintenance (a) replacement zone, for example folded conformation or helical conformation, (b) electric charge of target site molecule or hydrophobicity, or (c) on the effect of the volume of side chain marked difference is arranged.Naturally occurring residue is divided into groups based on common side chain character:

(1) hydrophobic residue: Nle, Met, Ala, Val, Leu, Ile;

(2) neutral hydrophilic residue: Cys, Ser, Thr;

(3) acidic residues: Asp, Glu;

(4) alkaline residue: Asn, Gln, His, Lys, Arg;

(5) influence the residue of chain orientation: Gly, Pro; With

(6) aromatic residues: Trp, Tyr, Phe.

Non-conservation replaces will bear the exchange to another kind of member with the member of one of these types.

Usually can improve the oxidative stability of molecule and prevent crosslinked unusually with the cysteine residues that Serine replaces the correct conformation do not participate in keeping antibody.Otherwise, the halfcystine key can be added and improve its stability (particularly when antibody be during) in the antibody such as antibody fragments such as Fv fragments.

One class substituted varient relates to the replacement of one or more hypervariable regions residue of female antibody (for example, humanized antibody or human antibodies).Usually, the gained varient that is selected to further exploitation will have the biological property with respect to the improvement of the female antibody that produces it.The facilitated method that produces this class substituted varient relates to the affinity maturation that uses phage display.In brief, site, several hypervariable region (for example, 6～7 sites) sudden change is produced all possible aminoacid replacement in each site.With the antibody mutation body that so produces with the unit price form as with each particle in the syzygy of gene III product of the M13 that encapsulates to show from filobactivirus.As disclosed herein the varient of phage display is screened its biological activity (for example, binding affinity) then.In order to identify the site, candidate hypervariable region of modifying usefulness, can carry out L-Ala scanning sudden change so that identify the hypervariable region residue that antigen is combined with remarkable contribution.Substituting is, or in addition, maybe advantageously the structure of antigen conjugates complex body is analyzed so that identify point of contact between antigen and the Z group.These contact residues and to close on residue be the material standed for that is used for the replacement of the technology set forth according to this paper.In case produced these varients, as described hereinly all varients are screened and can select the antibody with the superior character in one or more dependence tests be used for further exploitation.

The amino acid variation body of another kind of antibody is found in the one or more glycosyls in the antibody by disappearance and/or adds the original glycosylation general layout that non-existent one or more glycosylation sites in the antibody have changed antibody.

The glycosylation of antibody is generally N-connection or O-connection.N-connects being connected of the side chain be meant sugar moieties and asparagine residue.Tripeptide sequence Asn-X-Ser and Asn-X-Thr are used for the recognition sequence that the enzymatic of glycosyl and l-asparagine side chain is connected, and wherein X is any amino acid except that proline(Pro).Therefore, potential glycosylation site has been created in any existence in polypeptide in these tripeptide sequences.O-connects the connection that glycosylation is meant one of sugar such as N-acetylgalactosamine, semi-lactosi and hydroxy-amino-acid (the most common be Serine or Threonine, but also can use 5-oxyproline or 5-oxylysine).

Thereby it contains one or more above-mentioned tripeptide sequences and can be conveniently implemented in and add glycosylation site (being used for the glycosylation site that N-connects) in the antibody by changing aminoacid sequence.Thereby also can change (being used for the glycosylation site that O-connects) by in original antibody sequence, adding or replacing with one or more Serines or threonine residues.

It is desirable to modify antibody of the present invention, for example so that strengthen or reduce the antigen dependent cell mediated cell toxicity (ADCC) and/or the CDC (CDC) of antibody according to effector function.This can realize by introduce one or more aminoacid replacement in the Fc district of antibody.Substituting is, thereby can carries out through engineering approaches to having the also possible antibody with enhanced complement hemolysis ability and ADCC ability in two Fc district.See G.T.Stevenson etc., Anticancer Drug Des.3:219-230 (1989).

In order to increase the serum half-life of antibody, can in antibody (especially antibody fragment), add and remedy the receptors bind epi-position, for example United States Patent (USP) the 5th, 739, described in No. 277.As used herein, term " is remedied the receptors bind epi-position " and is meant IgG molecule (for example, IgG ₁, IgG ₂, IgG ₃Or IgG ₄) the epi-position in Fc district, this epi-position is responsible for increasing serum half-life in the body of described IgG molecule.

Joint be connected compound

GA target described herein agent can directly or come with antibody combining site covalently bound via joint.Can select suitable joint so that enough distances are provided between target agent and antibody.Formula: shown the general design of an embodiment of the joint that is used to prepare the GA target compound among the X-Y-Z, wherein X is a connection chain, and Y is a recognition group and Z is a reactive group.Joint can be a straight or branched, and randomly comprises one or more carbocylic radicals or heterocyclic radical.Can check length of said joint according to the number of straight chain atom, and by choosing along the shortest path of ring to come counting such as annular groups such as aromatic nucleus.In some embodiments, joint has 5～15 straight chain sections between the atom, be 15～30 atoms in other embodiments, in other embodiment is arranged again 30～50 atoms, be 50～100 atoms in other embodiment is arranged again, and be 100～200 atoms in other embodiment is arranged again.The consideration of other butt junction comprise effect on physical properties or pharmacokinetic property of gained GA target compound or GA target agent-joint, solvability, lipotropy, wetting ability, hydrophobicity, stability (more stable or more unstable and planned degraded), rigidity, flexibility, immunogenicity, antibodies adjusting, enter micella or the intravital ability of lipid or the like.

The connection chain X of joint comprises any atom or its salt from C, H, N, O, P, S, halogen (F, Cl, Br, I).X can also comprise such as groups such as alkyl, thiazolinyl, alkynyl, oxoalkyl group, oxo thiazolinyl, oxo alkynyl, aminoalkyl group, amino thiazolinyl, amino alkynyl, alkylthio, sulfo-thiazolinyl, sulfo-alkynyl, alkyl acid phosphate, phosphoric acid thiazolinyl or phosphoric acid alkynyls.In some embodiments, X can comprise one or more ring structures.In some embodiments, joint is such as comprising 2～100 repeating polymers such as unitary polyvinyl alcohol.

The recognition group Y of joint is optionally, and when existing between reactive group and connection chain.In some embodiments, there is 1～20 atom the position of Y away from Z.Although do not wish to be subjected to any theory, thereby it is believed that recognition group plays a part that reactive group is correctly navigated in the antibody combining site this reactive group and can react with reactive amino acid side chain.The example of recognition group comprises carbocyclic ring and the heterocycle that preferably has 5 or 6 atoms.Yet, also can use bigger ring structure.In some embodiments, use gets involved joint and the agent of GA target is directly linked to each other with Y.

Z can form covalent linkage with the reactive side chain of antibody combining site.In some embodiments; Z comprises one or more C=O groups, described C=O group be arranged to form diketone, acyl group-beta-lactam, active ester, halogenated ketone, cyclohexyl diketone base, aldehyde, maleimide, active olefin, activation alkynes or generally speaking comprise the molecule that is easy to by the leavings group of affine replacement or electrophilic substitution.Other group may comprise lactone, acid anhydrides, α-Lu Daiyixianan, imines, hydrazides or epoxide.Can with reactive nucleophilic group in the antibody combining site (for example; Methionin or cysteine side chain) the joint cationoid reaction examples of groups of covalent bonding comprises acyl group-beta-lactam; simple diketone; the succinimide active ester; maleimide; the Haloacetamide of belt lacing; halogenated ketone; cyclohexyl diketone; aldehyde; amidine; guanidine; imines; enamine; phosphoric acid ester; phosphonic acid ester; epoxide; ethylenimine; the sulfo-epoxide; shelter diketone or protection diketone (for example ketal); lactan; sulphonate or the like, the C=O group of sheltering is such as imines; ketal; acetal and any other known electrophilic group.In one embodiment; reactive group comprises one or more C=O groups, and described C=O group is arranged to form Haloacetamide, halogenated ketone, cyclohexyl diketone or the aldehyde of acyl group-beta-lactam, simple diketone, succinimide active ester, maleimide, belt lacing.

Select joint reactive group or this similar class reactive group to come the reactive residue in the particular combination site to use.For example, be used for to be ketone, diketone, beta-lactam, active ester halogenated ketone, lactone, acid anhydrides, maleimide, α-Lu Daiyixianan, cyclohexyl diketone, epoxide, aldehyde, amidine, guanidine, imines, enamine, phosphoric acid ester, phosphonic acid ester, epoxide, ethylenimine, sulfo-epoxide, to shelter diketone or protect diketone (for example ketal), lactan, halogenated ketone, aldehyde or the like by the chemical part of zymohexase antibody modification.

Be applicable to that chemical part by the joint reactive group of the reactive sulfydryl covalent modification in the antibody can be disulphide, aryl halide, maleimide, α-Lu Daiyixianan, isocyanic ester, epoxide, thioesters, active ester, amidine, guanidine, imines, enamine, phosphoric acid ester, phosphonic acid ester, epoxide, ethylenimine, sulfo-epoxide, shelter diketone or protection diketone (for example ketal), lactan, halogenated ketone, aldehyde or the like.

Those skilled in the art are with easy to understand, the reactive amino of antibody combining site acid side chain can have with the agent of GA target or its joint on the electrophilic group that reacts of nucleophilic group, yet the reactive nucleophilic group in the amino acid side chain and the electrophilic group in agent of GA target or the joint react in other embodiments.

Can prepare the GA target compound by several method.In one approach, synthesized GA target agent-linker compounds with joint, described joint comprises the one or more reactive groups that are designed for the covalent reaction of the amino acid side chain of antibody combining site.Joint reactive group and amino acid side chain form under the condition of covalent linkage and mix therein with target agent-linker compounds and antibody.

In another approach, can realize being connected by the synthetic antibody-linker compounds that comprises antibody and joint, wherein said joint comprises the one or more reactive groups that are designed for the covalent reaction of the chemical part of suitable GA target agent.The reaction that may need to GA target agent to be modified to the joint reactive group provides suitable part.Mix under the condition that antibody-joint and the agent of GA target joint reactive group and target agent therein and/or biological agent is covalently bound.

The another kind of method that is used to form antibody-GA target compound has been used the double-end design.In one embodiment, the GA target agent-linker compounds that has synthesized the joint that comprises the agent of GA target and have reactive group.Then synthesized and comprised antibody and having and be easy to antibody-linker compounds with the joint of the chemical group of the reaction-ity group reaction of the GA target agent-joint of the first step.To mix under these two compounds that the contain joint condition that the joint covalency links to each other therein then, thereby formed antibody-GA target compound.

The example that can participate in into the functional group of key for example comprises, ester group, amide group, ether, phosphate, amino, ketone group, amidine, guanidine radicals, imines, enamine, phosphoric acid ester, phosphonic acid ester, epoxide, ethylenimine, sulfo-epoxide, shelters diketone or protection diketone (for example ketal), lactan, halogenated ketone, aldehyde, thiocarbamate, thioamides, thioesters, sulfide, disulphide, phosphamide, sulphonamide, urea, thiocarbamide, carbamate, carbonic ether, oxyamide (hydroxyamide) or the like.

Joint comprises any atom or its salt from C, H, N, O, P, S, halogen (F, C1, Br, I).Joint can also comprise such as groups such as alkyl, thiazolinyl, alkynyl, oxoalkyl group, oxo thiazolinyl, oxo alkynyl, aminoalkyl group, amino thiazolinyl, amino alkynyl, alkylthio, sulfo-thiazolinyl, sulfo-alkynyl, alkyl acid phosphate, phosphoric acid thiazolinyl or phosphoric acid alkynyls.Joint can also comprise one or more ring structures." ring structure " as used herein comprises saturated carbon ring, unsaturated carbocyclic and aromatic carbocyclic and saturated heterocyclic, unsaturated heterocycle and aromatic heterocycle.Ring structure can be monocycle, dicyclo or many rings, and comprises condensed ring and non-condensed ring.In addition, ring structure is randomly replaced by functional group well known in the art, described functional group include but not limited to halogen, oxo ,-OH ,-CHO ,-COOH ,-NO ₂,-CN ,-NH ₂,-C (O) NH ₂, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Oxoalkyl group, oxo thiazolinyl, oxo alkynyl, aminoalkyl group, amino thiazolinyl, amino alkynyl, alkylthio, sulfo-thiazolinyl, sulfo-alkynyl, alkyl acid phosphate, phosphoric acid thiazolinyl or phosphoric acid alkynyl.The combination of above group and ring also may reside in the joint of GA target compound.

An aspect of of the present present invention is the GA target agent-joint conjugate with formula I:

The agent of L-[GA target] (I)

Wherein [agent of GA target] is GA target agent peptide.Suitable GA target agent peptide includes but not limited to analogue (comprising for example carboxyl truncate or mutant) and the GA target compound as herein described of SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:1 or SEQ ID NO:2.

Shank L can link to each other with the carboxyl terminal of GA target agent or the electric side chain of any parent or the nucleophilic side chain of its amino acid side.The tie point of L and the agent of GA target is called " tiing point (tethering point) " in this article.

In some embodiments, L links to each other with amino acid whose nucleophilic side chain or close electric side chain in the agent of GA target.The example of nucleophilic side chain is Lys, Cys, Ser, Thr and Tyr.In L and those embodiments that the nucleophilic side chain links to each other, L should comprise the electrophilic group that is easy to carry out with described nucleophilic side chain covalent reaction therein.The example of the electric side chain of parent is Asp and Glu.In L and those embodiments that the electric side chain of parent links to each other, L should comprise the nucleophilic group that is easy to carry out with the electric side chain of described parent covalent reaction therein.

In some embodiment that the nucleophilic side chain of L and the amino acid (being connected residue) of GA target agent links to each other, L links to each other with the nucleophilic side chain of Lys residue therein.Among in these embodiments some, described Lys residue is 20 or 28 residues of SEQ ID NO:1, perhaps 12 of SEQ IDNO:2 or 27 residues.In some other embodiment, the carboxyl terminal of the GA target agent of SEQ ID NO:1 or SEQ ID NO:2 or its analogue has inserted the Lys residue, and joint L links to each other with the side chain covalency of this additional amino acid.For example, in one embodiment, the agent of GA target is:

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK (SEQID NO:3), or

HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SEQ?ID?NO：4)。

SEQ ID NO:3 is identical with SEQ ID NO:2, except the carboxyl terminal at this polypeptide has inserted the Lys residue.SEQ ID NO:4 is identical with SEQ ID NO:3, except replaced 2 Gly residue with Aib2.

The examples for compounds that comprises based on the formula I of the target agent of SEQ ID NO:3 or SEQ ID NO:4 includes but not limited to:

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(L)(SEQ?ID?NO：166)；

HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK (L) (SEQ ID NO:167); With

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK-R ²(SEQ?IDNO：30)。

In some other embodiment, sentence insertion of Lys residue or replacement at the interior location of SEQ ID NO:1 or SEQ ID NO:2 or its analogue, and joint L links to each other with the side chain covalency of this additional amino acid.Shown in the following Table II of the example of these embodiments.A little the insertion Lys residue underscore tied in the connection of serving as joint L.

Table II

Have the GA target agent that Methionin replaces based on SEQ ID NO:1 and SEQ ID NO:2

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPP KS-R ²(SEQ?ID?NO：14)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGA KPPS-R ²(SEQ?ID?NO：15)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSS KAPPPS-R ²(SEQ?ID?NO：16)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGP KSGAPPPS-R ²(SEQ?ID?NO：17)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK KGGPSSGAPPPS-R ²(SEQ?ID?NO：18)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEW KKNGGPSSGAPPPS-R ²(SEQ?ID?NO：19)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFI KWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：20)

R ¹-HAibEGTFTSDLSKQMEEEAVRLF KEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：21)

R ¹-HAibEGTFTSDLSKQMEEEAVR KFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)

R ¹-HAibEGTFTSDLSKQMEEEAV KLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)

R ¹-HAibEGTFTSDLSKQMEEEA KRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)

R ¹-HAibEGTFTSDLSKQMEE KAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：25)

R ¹-HAibEGTFTSDLSKQME KEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)

R ¹-HAibEGTFTSDLSKQ KEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)

R ¹-HAibEGTFTSDLSK KMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：28)

R ¹-HAibEGTFTSDL KKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：29)

R ¹-HAibEGTFTSDLSKQMEEEAVR KFIEWLKNGGPSS-R ²(SEQ?ID?NO：31)

R ¹-HAibEGTFTSDVSSYLE KQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：47)

R ¹-HAibEGTFTSD KSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：64)

R ¹-HAibEGTFTSDVS KYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：65)

R ¹-HAibEGTFTSDVSSY KEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：66)

R ¹-HAibEGTFTSDVSSYLE KQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：67)

R ¹-HAibEGTFTSDVSSYLEEQ KVKEFIAWLIKAibR-R ²(SEQ?ID?NO：68)

R ¹-HAibEGTFTSDVSSYLEEQAVKE KIAWLIKAibR-R ²(SEQ?ID?NO：69)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFI KWLIKAibR-R ²(SEQ?ID?NO：70)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAW KIKAibR-R ²(SEQ?ID?NO：71)

In covalently bound those embodiments of Lys residue in joint L and the GA target peptide, this Lys residue can be the Lys that side chain is modified therein.Among in these embodiments some, the Lys that side chain is modified is:

In the compound of formula I, L is the shank with formula-X-Y-Z, wherein:

Z is the reactive group covalently bound with the side chain of antibody combining site.

In some embodiment of the compound of formula I, X is:

-R ²²-P-R ²³-or-R ²²-P-R ²¹-P '-R ²³-

Wherein:

R ²¹, R ²²And R ²³Be independently of one another covalent linkage ,-O-,-S-,-NR ^b-, replacement or unsubstituted straight or branched C _1-50Alkylidene group or replacement or unsubstituted straight or branched C _1-50Assorted alkylidene group;

In some embodiment of the mixture of formula I, R ²²Be-(CH ₂) _v-,-(CH ₂) _u-C (O)-(CH ₂) _v-,-(CH ₂) _u-C (O)-O-(CH ₂) _v-,-(CH ₂) _u-C (S)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-C (O)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-NR ^b-(CH ₂) _v-,-(CH ₂) _u-O-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-NR ^b-(CH ₂) _v-or-(CH ₂) _u-P (O) (OR ^b)-O-(CH ₂) _v-, wherein u and v are 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently of one another.

In other embodiment of the compound of formula I, R ²²Be-(CH ₂) _v-,-(CH ₂) _u-C (O)-(CH ₂) _v-,-(CH ₂) _u-C (O)-O-(CH ₂) _v-,-(CH ₂) _u-C (O)-NR ^b-(CH ₂) _v-or-(CH ₂) _u-NR ^b-(CH ₂) _vIn other embodiments, R ²²Be-(CH ₂) _u-C (O)-NR ^b-(CH ₂) _v-.

In some embodiment of the compound of formula I, R ²¹And R ²³Be independently of one another-(CH ₂) _s-,-(CH ₂) _r-C (O)-(CH ₂) _s-,-(CH ₂) _r-C (O)-O-(CH ₂) _v-,-(CH ₂) _r-C (S)-NR ^b-(CH ₂) _s-,-(CH ₂) _r-C (O)-NR ^b-(CH ₂) _s-,-(CH ₂) _r-NR ^b-(CH ₂) _s-,-(CH ₂) _r-O-(CH ₂) _s-,-(CH ₂) _r-S (O) _0-2-(CH ₂) _s-,-(CH ₂) _r-S (O) _0-2-NR ^b-(CH ₂) _s-or-(CH ₂) _r-P (O) (OR ^b)-O-(CH ₂) _s-, wherein r, s and v are 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently of one another.

In other embodiments, R ²¹And R ²³Be independently of one another-(CH ₂) _s-,-(CH ₂) _r-C (O)-(CH ₂) _s-,-(CH ₂) _r-C (O)-O-(CH ₂) _s-,-(CH ₂) _r-C (O)-NR ^b-(CH ₂) _s-or-(CH ₂) _r-NR ^b-(CH ₂) _sWith-(CH ₂) _r-C (O)-NR ^b-(CH ₂) _s-.

In other embodiments, R ²¹And R ²³Have structure independently of one another:

Wherein p is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,32,43,44 or 45; W, r and s are 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently of one another; And Rb is hydrogen, replacement or unsubstituted C at every turn independently when occurring _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.

In some embodiment of the compound of formula I, X has structure:

H wherein ¹And H ¹' be N, O, S or CH independently when occurring at every turn ₂R and s are 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently of one another; T and t ' are 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,32,43,44,45,46,47,48,49 or 50 independently of one another; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.

In some embodiment of the compound of formula I, X has structure:

H wherein ¹And H ¹' be N, O, S or CH independently when occurring at every turn ₂R and s are 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently of one another; T and t ' are 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,32,43,44,45,46,47,48,49 or 50 independently of one another; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.

In some embodiment of the compound of formula I, X has structure:

In some embodiment of the compound of formula I, X has structure:

In some embodiment of the compound of formula I, X has structure:

Wherein v and w are 1,2,3,4 or 5 and R independently of one another ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.Among in these embodiments some, v is 1,2 or 3, and w is 1,2 or 3, and R ^bBe hydrogen.

In some embodiment of formula I, L is the shank with formula X-Y-Z, wherein:

X links to each other with one of residue that constitutes the agent of GA target, and randomly by-R ²²-[CH ₂-CH ₂-O] _t-R ²³-,-R ²²-cycloalkyl-R ²³-,-R ²²-aryl-R ²³-or-R ²²-heterocyclic radical-R ²³-replace, wherein:

R ²²And R ²³Be independently of one another covalent linkage ,-O-,-S-,-NR ^b-, replacement or unsubstituted straight or branched C _1-50Alkylidene group, replacement or unsubstituted straight or branched C _1-50Assorted alkylidene group, replacement or unsubstituted straight or branched C _2-50Alkenylene or replacement or unsubstituted C _2-50Assorted alkenylene;

T is 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,32,43,44,45,46,47,48,49 or 50;

And R ²²And R ²³Size make the backbone length of X be maintained at about 200 atoms or about 200 below the atom;

Z is the reactive group that can link to each other with the side chain covalency of antibody combining site.

In some embodiment of the compound of formula I, if if t＞1 or-X is-R ²²-cycloalkyl-R ²³-,-R ²²-aryl-R ²³-or-R ²²-heterocyclic radical-R ²³-, then Y exists.

In some embodiment of the compound of formula I, X is:

-R ²²-[CH ₂-CH ₂-O] _t-R ²³-，

Wherein:

R ²²Be-(CH ₂) _v-,-(CH ₂) _u-C (O)-(CH ₂) _v-,-(CH ₂) _u-C (O)-O-(CH ₂) _v-,-(CH ₂) _u-C (O)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-C (S)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-NR ^b-(CH ₂) _v-,-(CH ₂) _u-O-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-NR ^b-(CH ₂) _v-or-(CH ₂) _u-P (O) (OR ^b)-O-(CH ₂) _v-;

U and v be independently of one another 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 and t be 0～50.

R ²³Have structure:

Wherein:

P is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,32,43,44 or 45;

W and r are 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20 independently of one another;

S is 0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19 or 20; And

R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl;

And thereby the value of selecting t, u, w, p, v, r and s makes the X backbone length be maintained at about 200 atoms or 200 below the atom.

In an embodiment of the compound of formula I, X has formula:

Thereby the value of wherein selecting v, t, w and p makes the X backbone length less than 200 atoms, and substituting is less than 100 atoms, and substituting is less than 75 atoms, or substituting be less than 50 atoms.

In another embodiment of the compound of formula I, X has formula:

Thereby the value of wherein selecting v, t, r and s makes the X backbone length less than 200 atoms, and substituting is less than 100 atoms, and substituting is less than 75 atoms, or substituting be less than 50 atoms.

In another embodiment of the compound of formula I, X has formula:

Thereby the value of wherein selecting u, v, t, w and p makes the X backbone length less than 200 atoms, and substituting is less than 100 atoms, and substituting is less than 75 atoms, or substituting be less than 50 atoms.

In another embodiment of the compound of formula I, X has formula:

Thereby the value of wherein selecting u, v, t, r and s makes the X backbone length less than 200 atoms, and substituting is less than 100 atoms, and substituting is less than 75 atoms, or substituting be less than 50 atoms.

In another embodiment of the compound of formula I, X has formula:

In another embodiment of the compound of formula I, X has formula:

In some embodiment of the compound of formula I, X has structure:

Thereby the value of wherein selecting u, v, t, w and p makes the X backbone length less than 200 atoms, substituting is less than 100 atoms, and substituting is less than 75 atoms, and substituting is less than 50 atoms, substituting is less than 25 atoms, or substituting be less than 15 atoms.

In some embodiment of the compound of formula I, X has structure:

Thereby the value of wherein selecting u, v, t, r and s makes the X backbone length less than 200 atoms, substituting is less than 100 atoms, and substituting is less than 75 atoms, and substituting is less than 50 atoms, substituting is less than 25 atoms, or substituting be less than 15 atoms.

In some embodiment of the compound of formula I, X has structure:

In some embodiment of the compound of formula I, X has structure:

In another embodiment of the compound of formula I, X has formula:

In another embodiment of the compound of formula I, X has formula:

L has in the compound with formula I of formula-X-Y-Z therein, and the ring structure of Y comprises saturated carbon ring, unsaturated carbocyclic and aromatic carbocyclic and saturated heterocyclic, unsaturated heterocycle and aromatic heterocycle.Ring structure can be monocycle, dicyclo or many rings, and comprises condensed ring and non-condensed ring.In addition, ring structure is randomly replaced by functional group well known in the art, described functional group include but not limited to hydrogen, oxo ,-OH ,-CHO ,-COOH ,-NO ₂,-CN ,-NH ₂, amidino groups, guanidine radicals, hydroxylamino ,-C (O) NH ₂, secondary amide base and teritary amide base, sulfoamido, replacement or not substituted alkyl, replacement or unsubstituting ene yl, replacement or unsubstituting polysulfide yl, oxoalkyl group, oxo thiazolinyl, oxo alkynyl, aminoalkyl group, amino thiazolinyl, amino alkynyl, alkylthio, sulfo-thiazolinyl, sulfo-alkynyl, alkyl acid phosphate, phosphoric acid thiazolinyl and phosphoric acid alkynyl.

In some embodiment of the compound with formula I, the ring structure of Y has the optional following formula that replaces:

Wherein

A, b, c, d and e are carbon or nitrogen independently; And

F is carbon, nitrogen oxygen or sulphur;

Y links to each other at any two ring position places of enough valence states with Z with X independently; And

Be no more than four among a, b, c, d, e or the f and be nitrogen simultaneously.

Constitute on the atom of ring structure remaining any open valence state can by hydrogen or other substituting group or with fill X and being connected of Z.For example, if b is a carbon, then its valence state can be by hydrogen, such as substituting groups such as hydrogen, fill with the covalent linkage of X or with the covalent linkage of Z.In some embodiments, a, b, c, d and the e carbon of respectively doing for oneself, and in other embodiments, a, c, d and the f carbon of respectively doing for oneself.In other embodiments, one of a, b, c, d or e are nitrogen at least, and in also having other embodiment, f is oxygen or sulphur.In another embodiment, the ring structure of Y is not substituted.In one embodiment, Y is a phenyl.

In some embodiment of the compound of formula I, X-Y has structure:

Among in these embodiments some, v is 1,2,3,4 or 5; W is 1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some other embodiment, v be 1,2 or 3 and w be 1,2 or 3.In other embodiments, v be 1 or 2 and w be 1 or 2.

In some embodiment of the compound of formula I, X-Y has structure:

H wherein ¹And H ¹' be N, O, S or CH independently of one another ₂R and s are 1,2,3,4 or 5 independently of one another; And t and t ' are 0,1,2,3,4 or 5 independently of one another.Among in these embodiments some, H ¹And H ¹' be O or CH independently of one another ₂R and s are 1 or 2 independently of one another; And t and t ' are 0 or 1 independently of one another.

In some embodiment of the compound of formula I, X-Y has structure:

H wherein ¹And H ¹' be N, O, S or CH independently of one another ₂R and s are 1,2,3,4 or 5 independently of one another; T and t ' are 0,1,2,3,4 or 5 independently of one another, and R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.Among in these embodiments some, H ¹And H ¹' be O or CH independently of one another ₂R and s are 1 or 2 independently of one another; And t and t ' are 0 or 1 independently of one another.

In some embodiment of the compound of formula I, X-Y has structure:

In some embodiment of the compound of formula I, X-Y has structure:

In some embodiment of the compound of formula I, X-Y has structure:

H wherein ¹And H ¹' be N, O, S or CH independently of one another ₂R and s are 1,2,3,4 or 5 independently of one another; T and t ' are 0,1,2,3,4 or 5 independently of one another, and R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.Among in these embodiments some, H ¹And H ¹' be O or CH independently of one another ₂R and s are 1 or 2 independently of one another; And t and t ' are 0 or 1 independently of one another.

In some embodiment of the compound of formula I, X-Y has structure:

In these embodiments of the compound of some formula I, X-Y has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5, and R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; W is 1; And p is 3.In some embodiments, v is 0; T is 1,2 or 3, w is 1; And p is 1 or 2.

In some embodiment of the compound of formula I, X-Y has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; And s is 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; And s is 1 or 2.

In some embodiment of the compound of formula I, X-Y has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; W is 1; And p is 3.In some embodiments, u is 0 or 1; V is 0; T is 1 or 2; W is 1; And p is 1 or 2.

In some embodiment of the compound of formula I, X-Y has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; And s is 3.In some embodiments, u is 0 or 1; V is 0; T is 1,2 or 3; R is 1; And s is 1 or 2.

In some embodiment of the compound of formula I, X-Y has structure:

In some embodiment of the compound of formula I, X-Y has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; And s is 3.In some embodiments, u is 0 or 1; V is 0; T is 1,2 or 3, r is 1; And s is 1 or 2.

In some embodiment of the compound of formula I, X-Y has structure:

In some embodiment of the compound of formula I, X-Y has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; And s is 3.In some embodiments, u is 0 or 1; V is 0; T is 1,2 or 3, r is 1; And s is 1 or 2.

In some embodiment of the compound of formula I, X-Y has structure:

In some embodiment of the compound of formula I, X-Y has structure:

In some embodiment of the compound of formula I, X-Y has structure:

In one embodiment, X-Y has formula:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 0 or 1.

L has in the compound with formula I of formula-X-Y-Z therein, and reactive group Z contains the part that can form covalent linkage with the amino acid of antibody combining site.For example; Z can be substituted alkyl, substituted cycloalkyl, substituted aryl, substituted aralkyl, substituted heterocyclic radical or substituted heterocyclic radical alkyl; wherein at least one substituting group is 1,3-diketone part, acyl group-beta-lactam, active ester, α-Lu Daitong, aldehyde, maleimide, lactone, acid anhydrides, α-Lu Daiyixianan, amine, hydrazides or epoxide.In some this class embodiment, Z is a substituted alkyl.

Z can be the group that forms reversible or irreversible covalent linkage.In some embodiments, can use all those diketone Z bases as shown in Figure 7 to form reversible covalent bonds.Therefore, structure A～C can form reversible covalent bonds with the reactive nucleophilic group (for example, Methionin or cysteine side chain) in the antibody combining site.R ' among the structure A of Fig. 7～C ₁, R ' ₂, R ₃And R ₄Expression can be the substituting group of C, H, N, O, P, S, halogen (F, Cl, Br, I) or its salt.These substituting groups also can comprise such as groups such as alkyl, thiazolinyl, alkynyl, oxoalkyl group, oxo thiazolinyl, oxo alkynyl, aminoalkyl group, amino thiazolinyl, amino alkynyl, alkylthio, sulfo-thiazolinyl or sulfo-alkynyl, alkyl acid phosphate, phosphoric acid thiazolinyl or phosphoric acid alkynyls.R ' ₂And R ₃Also can form ring structure as structure B and C illustrated.X among Fig. 7 can be a heteroatoms.Other Z base that can form reversible covalent bonds comprises amidine, imines and other reactive group of being contained by the structural formula G of Fig. 7.Fig. 8 has comprised the structure of other joint reactive group that forms reversible covalent bonds, for example, structure B, G, H and wherein X be not the E and the F of leavings group.

Can comprise structure D～G (for example, when G is imines ester (imidate)) among Fig. 7 and structure A, C and the D of Fig. 8 with the Z reactive group that antibody combining site forms irreversible covalent linkage.When X was leavings group, the structure E of Fig. 8 and F also can form irreversible covalent linkage.These structures can be used for target agent-joint is irreversibly linked to each other with reactive nucleophilic group in the antibody combining site.

In other this class embodiment, Z is 1,3-diketone part.In other these embodiments again, Z is by 1, the alkyl that 3-diketone part is replaced.In one embodiment, Z has structure:

Q=0～5 wherein.In another embodiment, Z has structure:

A kind of joint that is used for the GA target compound and is used to prepare GA target agent-linker compounds comprises 1, and 3-diketone reactive group is as Z.In the embodiment of formula I, L has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; W is 1; P is 3; And q is 0,1,2 or 3.In some embodiments, v is 0; T is 1 or 2; W is 1; P is 1 or 2; And q is 1 or 2.

In some embodiment of formula I, L has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; Q is 0,1,2 or 3; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; W is 1; P is 3; And q is 0,1,2 or 3.In some embodiments, v is 0; T is 1 or 2; W is 1; P is 1 or 2; And q is 2 or 3.

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 3; And q is 0,1,2 or 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 1 or 2.

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2 or 3; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 3; And q is 0,1,2 or 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 2 or 3.

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; W is 1; P is 3; And q is 0,1,2 or 3.In some embodiments, u is 0 or 1; V is 0; T is 1 or 2; W is 1; P is 1 or 2; And q is 1 or 2.

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; W is 1; P is 3; And q is 0,1,2 or 3.In some embodiments, v is 0; T is 1 or 2; W is 1; P is 1 or 2; And q is 1 or 2.

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; Q is 0,1,2 or 3; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; W is 1; P is 3; And q is 0,1,2 or 3.In some embodiments, v is 0; T is 1 or 2; W is 1; P is 1 or 2; And q is 2 or 3.

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,5 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 3; And q is 0,1,2 or 3.In some embodiments, u is 0 or 1; V is 0; T is 1 or 2; W is 1; P is 1 or 2; And q is 1 or 2.

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,5 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 3; And q is 0,1,2 or 3.In some embodiments, u is 0 or 1; V is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 1 or 2.

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,5 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2 or 3; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 3; And q is 0,1,2 or 3.In some embodiments, u is 0 or 1; V is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 2 or 3.

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; Q is 0,1,2 or 3; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; W is 1; P is 3; And q is 0,1,2 or 3.In some embodiments, u is 0 or 1; V is 0; T is 1 or 2; W is 1; P is 1 or 2; And q is 2 or 3.

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,5 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 3; And q is 0,1,2 or 3.In some embodiments, u is 0 or 1; V is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 1 or 2.

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,5 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2 or 3; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 3; And q is 0,1,2 or 3.In some embodiments, u is 0 or 1; V is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 2 or 3.

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C0-6 alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; W is 1; P is 3; And q is 0,1,2 or 3.In also having some embodiment, u is 0 or 1; V is 0; T is 1 or 2; W is 1; P is 1 or 2; And q is 1 or 2.

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

Among in these embodiments some, u is 0,1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 0; V is 0; T is 1,2,3,4,5 or 6; W is 1; P is 3; And q is 0,1,2 or 3.In other embodiments, u is 0 or 1; V is 0; T is 1 or 2; W is 1; P is 1 or 2; And q is 1 or 2.

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 0; And q is 0,1,2 or 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1 or 2; S is 0; And q is 1 or 2.

In some embodiment of formula I, L has structure:

In some embodiment of formula I, L has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 3; And q is 0,1,2 or 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 1 or 2.

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2 or 3; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 3; And q is 0,1,2 or 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 2 or 3.

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Another embodiment according to formula I is:

Wherein v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; And q is 0,1,2,3,4 or 5.Among in these embodiments some, v is 0; T is 1,2,3,4,5 or 6; W is 1; P is 3; And q is 2.

Used herein

Be meant the agent of GA target, wherein " AA ₁" be to hold first amino acid of counting the GA target agent sequence, " AA from N ₂" be that the N end is counted second amino acid in the GA target agent sequence, and " AA _n" be that the N end is counted n amino acid in the GA target agent sequence.This target agent also comprises the Lys residue of holding the optional position m+1 of counting from N.Be understandable that except with Lys side chain in the GA target agent main body links to each other, also may link to each other with the N end of GA target agent or the Lys side chain on the C end.

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula II has structure:

Among in these embodiments some, u is 1,2,3,4 or 5; V is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, u is 1,2,3,4 or 5; V is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S is 0; And q is 0,1,2 or 3.In some embodiments, u is 1,2 or 3; V is 0; T is 1,2 or 3, r is 1 or 2; S is 0; And q is 1 or 2.

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

In some embodiments, the joint L according to formula 1 is:

The immunocompetence individuality is used the antibody that the GA target compound may cause generating anti-described conjugate.These antibody targetedly can be comprised the variable region and the target agent of antibody idiotype or be used for any joint with target agent and antibody coupling.Can be by approach well known such as realizing immunogenic reduction to the GA target compound by linking to each other with the GA target compound based on transcribed spacer of longer chain polyethylene glycols (PEG) or the like.Thereby having, known long-chain PEG and other polymkeric substance shelter ability (N.V.Katre, the J.Immunol.144:209-213 (1990) that external epi-position causes the immunogenicity of the human cytokines of showing external epi-position to reduce; G.E.Francis etc., Int.J.Hematol.68:1-18 (1998)).Substituting is, or additivity is to use such as immunosuppressor such as ciclosporin A, anti-cd 3 antibodies the individuality of having used antibody-GA target agent conjugate.

In one embodiment, the GA target compound is suc as formula shown in the II, and comprises its steric isomer, tautomer, solvate, prodrug and pharmacologically acceptable salt.

Antibody-L '-[agent of GA target] (II)

In the compound of formula II, [agent of GA target] suc as formula defining among the I, and L ' be antibody is linked to each other with the target agent and have formula-X-Y-Z '-shank.In the compound of formula II, X and Y are suc as formula defining among the I, and antibody (Antibody) is antibody defined herein.Fig. 9 and Figure 10 have shown addition mechanism in the Z group that the reactive nucleophilic residues in the antibody combining site shows respectively in Fig. 7 and Fig. 8.

In one embodiment, wherein antibody is the zymohexase catalytic antibody, and Z '-antibody has formula:

In the compound with formula II, Z ' is the connection portion that comprises covalent linkage and 0～20 carbon atom that links to each other with antibody.Have diketone part the situation that is connected for its center tap as the side chain amino of the lysine residue in reactive group (seeing the Z of formula I) and existence and the antibody combining site, as follows.Schematically illustrate the antibody that each indicated binding site is become divalence with reactive amino acid side chain.

Another embodiment as follows is used for its center tap and has beta-lactam part as reactive group and the existence situation that is connected with the side chain amino of the lysine residue of antibody combining site.The exemplary antibody that each indicated binding site is become divalence with reactive amino acid side chain that shown.

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; W is 1,2,3,4 or 5; P is 1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; W is 1; And p is 3.In some embodiments, v is 0; T is 1 or 2; W is 1; And p is 1 or 2.

Some embodiment according to formula II has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S be 3 and q be 0,1,2 or 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 1 or 2.

Some embodiment according to formula II has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2 or 3; And R ^bBe hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S be 3 and q be 0,1,2 or 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 2 or 3.

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S be 3 and q be 0,1,2 or 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 1 or 2.

Some embodiment according to formula II has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; Q is 0,1,2 or 3; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; S be 3 and q be 0,1,2 or 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; S is 1 or 2; And q is 2 or 3.

Some embodiment according to formula II has structure:

Among in these embodiments some, v is 0,1,2,3,4 or 5; T is 1,2,3,4,5 or 6; R is 1,2,3,4 or 5; S is 0,1,2,3,4 or 5; And R ^bWhen occurring, be hydrogen, replacement or unsubstituted C independently at every turn _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement or unsubstituted aryl-C _0-6Alkyl.In some embodiments, v is 0; T is 1,2,3,4,5 or 6; R is 1 or 2; And s is 3.In some embodiments, v is 0; T is 1,2 or 3, r is 1; And s is 1 or 2.

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula I has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Some embodiment according to formula II has structure:

Substituting is, joint can have as the amine of reactive group or hydrazides and antibody engineeringization can be had the diketone part.Can use the alpha-non-natural amino acid that approach well known will contain diketone easily to add antibody combining site; The albumen that will contain alpha-non-natural amino acid is introduced in yeast and the bacterium.For example see J.W.Chin etc., Science 301:964-966 (2003); L.Wang etc., Science 292:498-500 (2001); J.W.Chin etc., J.Am.Chem.Soc.124:9026-9027 (2002); L.Wang, etc., J.Am.Chem.Soc.124:1836-1837 (2002); J.W.Chin and P.G.Schultz, Chembiochem.3:1135-1137 (2002); J.W.Chin etc., Proc.Natl.Acad.Sci.U.S.A.99:11020-11024 (2002); L.Wang and P.G.Schultz, Chem.Commun. (1): 1-11 (2002); Z.Zhang etc., Angew.Chem.Int.Ed.Engl.41:2840-2842 (2002); L.Wang, Proc.Natl.Acad.Sci.U.S.A.100:56-61 (2003).Therefore; for example, insert the new constituent adding protein biology synthesis mechanism that S. cervisiae (Saccharomycescerevisiae) needs will comprise unique codon, tRNA and Anji acyl group-tRNA synthetic enzyme (aaRS) for the alpha-non-natural amino acid that will contain the diketone part.For example, can use from colibacillary amber inhibitor tyrosyl-tRNA synthetase (TyrRS)-tRNA eukaryote _CUARight, as J.W.Chin etc., reports among the Science 301:964-966 (2003).Amber codon is used for interested alpha-non-natural amino acid coding.Can produce mutant TyrRS and tRNA then _CUAThe storehouse and select wherein that TyrRS charges into tRNA with interested alpha-non-natural amino acid (amino acid that for example, contains diketone) _CUAThose aaRS-tRNA _CUARight.Subsequently, gene that can be by will containing described amber codon is the clone of one or more antibody combining sites place and express to produce and added the amino acid whose antibody that contains diketone.

At antibody described in some embodiment of the compound of formula II is full length antibody.In other embodiments, described antibody is Fab, Fab ' F (ab ') ₂, Fv, V _H, V _LOr scFv.In other embodiments, described antibody is human antibodies, humanized antibody or chimeric human antibodies.In other embodiments, described antibody is catalytic antibody.In one embodiment, described antibody is to comprise from IgG, IgA, IgM, the humanization form of the mouse 38c2 of the constant region of IgD or IgE antibody.In another embodiment, described antibody is to comprise from the variable region of mouse 38c2 with from IgG, IgA, IgM the chimeric antibody of the constant region of IgD or IgE antibody.

In some cases, the agent of two or more GA target can be linked to each other with single total length bivalent antibody.This is with shown in the following formula III:

Antibody [L '-[agent of GA target]] ₂(III)

Its steric isomer, tautomer, solvate, prodrug and pharmacologically acceptable salt are provided in addition.

In the compound of formula III, [agent of GA target], L ' and antibody are separately suc as formula defining among the II.

All target compounds such as those compounds suc as formula II can also by with target agent-joint and multivalent antibody binding site covalently bound come easily synthetic.For example, normal such as zymohexase antibody incubations such as h38C2IgG1 generation GA target compound thereby its center tap can be comprised the reactive target agent-joint conjugate partly of diketone with 0.5.Substituting is, can be by covalently bound generation of each binding site with GA target agent-linker compounds as described herein and bivalent antibody such as the GA target compounds such as those compounds of formula III.

The pharmaceutical composition of GA target compound

Another aspect of the present invention provides the pharmaceutical composition of GA target compound.Can use the technology of well known to a person skilled in the art to use the GA target compound.Preferably with reagent system ground prescription with use.The technology that is used to fill a prescription and uses can be in Remington ' sPharmaceutical Sciences, 18 ^ThEd., 1990, Mack Publishing Co., Easton finds among the PA.For injection, can be the aqueous solution, emulsion or suspension with GA target compound prescription.Preferably with GA target compound prescription in the aqueous solution that contains such as physiological compatibility damping fluids such as Citrate trianion, acetate, Histidine or phosphoric acid salt.In case of necessity, these preparations also (for example can contain various tension regulators, solubilizing agent and/or stablizer, such as salt such as sodium-chlor, such as sugar such as sucrose, N.F,USP MANNITOL and trehaloses, such as albumen such as albumin, such as amino acid such as glycine and Histidines, such as polysorbate tensio-active agents such as (Tweens), or such as solubility promoters such as ethanol, polyoxyethylene glycol and propylene glycol).

The using method of GA target compound

One aspect of the present invention is the method that is used for the treatment of diabetes or diabetes associated conditions, and described method comprises the GA target compound to the study subject administering therapeutic significant quantity of suffering from diabetes or diabetes associated conditions.Use for the treatment in the mankind, the antibody formation of preferred target compound is human antibodies, humanized antibody or chimeric human antibody.

Another aspect of the present invention is the method that is used for increasing the study subject insulin secretion, and described method comprises the GA target compound of study subject administering therapeutic significant quantity or its medicaments derivative.

Of the present invention is the method that is used for reducing study subject blood sugar more on the one hand, and described method comprises GA target compound or its medicaments derivative that study subject is used the treatment significant quantity.

Application process and dosage

The route of administration of GA target compound can comprise that parenteral is carried conveying in (comprising intramuscularly, subcutaneous injection or intramedullary injection) and the sheath, directly the ventricles of the brain are carried, intravenously is carried and intraperitoneal is carried.In one embodiment, using is that intravenously is used.Can by the direct injection preparation or by instillation target GA compound formulation and instillation matrix (such as common salt solution, D5W, Lactated Ringer'S Solution or other instillation medium commonly used) thus mixture use the GA target compound through any parenteral approach.

Treatment suffer from diabetes or diabetes associated conditions comprise human Mammals the time, used the GA target compound or the pharmaceutically acceptable derivative of treatment significant quantity.For example, can be with the GA target compound as using from intravenous drip every day of about 0.1mg/kg body weight～15mg/kg body weight.So an embodiment provides the dosage of about 0.5mg/kg body weight.Another embodiment provides the dosage of about 0.75mg/kg body weight.Another embodiment provides the dosage of about 1.0mg/kg body weight.Another embodiment provides the dosage of about 2.5mg/kg body weight.Another embodiment provides the dosage of about 5mg/kg body weight.Another embodiment provides the dosage of about 10.0mg/kg body weight.Another embodiment provides the dosage of about 15.0mg/kg body weight.Should perhaps use to mensal interval with weekly approximately alternatively with the dosage of GA target compound or pharmaceutically acceptable derivative to use to 2 times interval weekly approximately once a day.In one embodiment, thus having used doses has reached the peak plasma concentrations according to GA target compound of the present invention or its pharmaceutically acceptable derivative from about 0.002mg/mL～30mg/mL.This can carry out aseptic injection at the solution in the suitable preparation and realize (can use chemical field any appropriate formulation solution known to the skilled) by using composition.Can keep the desired blood level by continuous drip GA target compound according to the present invention, described blood levels is determined by the blood plasma level of measuring by effective analytical procedure.

Be used for to a kind of method that individuality is used the GA target compound comprise to individuality use GA target agent-joint conjugate and make it and body in suitably the binding site of antibody form covalent compound.Can with the antibody moiety of the GA target compound that forms in vivo before using target agent-joint conjugate, simultaneously or afterwards individuality is used.Discuss, the agent of GA target can comprise joint/reactive part, or suitably the modified antibodies binding site so that link to each other with target agent covalency.Substituting is that perhaps in addition, antibody may appear in the individual circulation carry out immunity with suitable antigen after.For example, can produce catalytic antibody by carrying out immunity with reactive intermediate with the substrate of carrier protein couplet.See R.A.Lerner and C.F.Barbas3 ^Rd, Acta Chem.Scand.50:672-678 (1996).Particularly, can produce the zymohexase catalytic antibody by using with the keyhole limpet hemocyanin (keyhole limpet hemocyanin) that has connected the diketone part, as P.Wirsching etc., described in the Science 270:1775-1782 (1995) (to J.Wagner etc., the comment of Science 270:1797-1800 (1995)).

Combination treatment

In another aspect of this invention, the therapeutical agent that GA target compound and other can be used for the treatment of diabetes or diabetes associated conditions or be used to increase insulin secretion or lowering blood glucose level is used in combination.In one embodiment, can be with the GA target compound and such as synthetic insulin human Regular Insulin combined administrations such as (comprising ultrashort effect, fugitive, middle effect or protamine zine insulin).In other embodiments, can be with GA target compound and the compound combined administration that belongs to alpha-glucosidase inhibitor, sulfonylurea, meglitinide, biguanides or thiazolidinedione (TZD) family.Can also and regulate metabolism such as albumen (GKRP), uncoupling protein 2 and 3 (UCP2 and UCP3), peroxisome proliferator-activated receptor alpha (PPAR α), leptin receptor (OB-Rb), DPP-IV inhibitor, sulfonylurea or other incretin peptide such as glucokinase (GK), glucokinase and modify property albumen or peptide combined administration the GA target compound.Those of ordinary skills should understand the various reagent in the treatment that is used in diabetes or diabetes associated conditions at present.

In order to estimate and the GA target compound of other therapeutical agent combination that is used for the treatment of diabetes or diabetes associated conditions, increase insulin secretion or lowering blood glucose level or the possible result of treatment of its pharmaceutically acceptable derivative, can use means known in the art to come these combinations are tested.For example, the insulin secretion that can use extracorporeal glucose to stimulate is tested the ability that increases insulin secretion according to the combination of GA target compound of the present invention and another kind of therapeutical agent of measuring.In such test, in the period of setting, handle pancreatic beta cell with the glucose of various concentration, use such as means known in the art such as radioimmunoassays then and measure insulin level.Thereby also can measure the effect on insulin secretion in vivo by the insulin level in the humoral sample of reagent directly being used and measured different time points to study subject according to GA target compound of the present invention and other therapeutical agent.The used method of combined therapy that is used for the known treatment agent is used study subject is that clinical healthcare provider is known.

The effective dose of GA target compound to be administered can be determined by well known to a person skilled in the art the isoparametric method of processing such as biological half-life, biological effectiveness and toxicity.The significant quantity of the therapeutical agent that is used in combination with GA target compound or its pharmaceutically acceptable derivative is based on the recommended dose to these therapeutical agents well known by persons skilled in the art.After the validity of having tested with these dosage of GA target compound of the present invention or pharmaceutically acceptable derivative combination, preferably these recommended amounts or known level are reduced 10%～50% of the dosage quoted.Should be noted that how and when the attending doctor will be appreciated that because of toxicity, marrow function disorder, liver dysfunction or kidney disorder or bad drug-drug interactions stops, interrupts or adjust treatment to reduce dosage.Otherwise the attending doctor also will be appreciated that if clinical response deficiency then treatment is adjusted to higher level (strick precaution toxicity).

The treatment effective dose is meant the compound amount that is enough to cause doing well,improving or the prolongation of patient's survival time.Can be by measuring effective bulk concentration that EC50 determines the agent of GA target.These reagent toxicity and result of treatment in vivo can be determined by operative norm pharmaceutical methods on cell culture or laboratory animal, for example is used for determining the method for LD50 (making 50% the lethal dosage of colony) and ED50 (the effective dosage of colony's treatment 50%).Dosage ratio between toxic effect and the result of treatment is a therapeutic index, and it can be expressed as ratio LD50/ED50.Preferably demonstrate the compound of big therapeutic index.The data that obtain from these cell culture tests and zooscopy can be used to prepare the dosage range that is used for the mankind.The dosage of these compounds preferably is in and has comprised ED50 and have few toxicity or do not have in the scope of toxic circulation composition.Dosage may change in this scope with the route of administration of being utilized according to the formulation that is adopted.For any compound, can come the treatment effective dose is carried out according to a preliminary estimate from the cell culture test.Doses can be administered in the animal model circulating plasma concentration range that has comprised IC50 (promptly compare with untreated contrast, that determines reaches concentration to half maximum test compounds that suppresses of the RT that produces from cells infected) to reach in cell culture.Can use these information to come more accurately to determine useful dosage among the mankind.Can be for example measure level in the blood plasma by high performance liquid chromatography (HPLC).

Therein in those embodiments of GA target compound and other therapeutical agent combined administration, can use following equation to calculate described combination of agents effect by the multiple drug analytical procedure (T.C.Chou and P.Talalay, Adv.Enzyme Regul.22:27-55 (1984)) of Chou and Talalay:

CI = \frac{D_{1}}{{(Dx)}_{1}} + \frac{D_{2}}{{(Dx)}_{2}} + \frac{α D_{1} D_{2}}{{(Dx)}_{1} {(Dx)}_{2}}

Wherein, CI is a combinatorial index, (Dx) ₁Be the dosage that produces the required medicine 1 of the effect of x% separately, D ₁Be and D ₂Combination and produce the dosage of the required medicine 1 of the effect of identical x%.(Dx) ₂(D) ₂Value derive from medicine 2 similarly.Use following intermediate value effect equation from the figure of dose effect curve, to determine the value of α:

\frac{fa}{fu} = {(\frac{D}{Dm})}^{m}

Wherein fa is the part that influenced by dosage D, and fu is unaffected part, and Dm is the required dosage of 50% effect, and m is the dose effect slope of a curve.For mutual exclusion medicine (being similar binding mode), two kinds of medicines separately and their mixture in intermediate value effect figure, provide parallel lines.Non-exclusive medicine (promptly independently binding mode) will provide parallel lines in intermediate value effect figure, but mixture will provide concave curve.If reagent mutual exclusion then α is 0, and if their not mutual exclusions then α is 1.Suppose that the value that not mutual exclusion obtains is always slightly high than mutual exclusion medicine.The CI value shows synergistic effect less than 1, and the CI value shows antagonistic effect greater than 1, and the CI value equals 1 and shows synergistic effect.

Can use also that (Cambridge, CalcuSyn software package UK) comes the calculation combination effect of drugs from Biosoft.

Embodiment

Embodiment 1:HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR's (SEQ IDNO:1) is synthetic

The solid-phase polypeptide that uses the Fmoc chemistry to adopt the PL-Rink resin (0.68mmol/g, Polymer Laboratories) of Fmoc protection to carry out modified peptides on the Symphony Peptide synthesizer on the scale of 100mol synthesizes.In synthetic, utilized following N ^αThe amino acid of-Fmoc protection: Fmoc-Arg (Pbf)-OH; Fmoc-Gly-OH; Fmoc-Lys (Boc)-OH; Fmoc-Val-OH; Fmoc-Leu-OH; Fmoc-Trp (Boc)-OH; Fmoc-Ala-OH; Fmoc-Ile-OH; Fmoc-Phe-OH; Fmoc-Glu (tBut)-OH; Fmoc-Gln-OH; Fmoc-Gly-OH; Fmoc-Leu-OH; Fmoc-Tyr (tBut)-OH; Fmoc-Ser (tBut)-OH; Fmoc-Asp (tBut)-OH; Fmoc-Thr (tBut)-OH and Fmoc-His (Trt)-OH.In brief, use 10 normal amino acid and 10 normal activator O-benzotriazole-1-base-N, N, N ¹, N ¹-tetramethyl-urea phosphofluoric acid ester (HBTU) and N-hydroxybenzotriazole (HOBT) carry out linked reaction in N-Methyl pyrrolidone (NMP) in the presence of 30 normal N-methylmorpholines (NMM), each coupling was carried out 2 hours.Use the piperidines nmp solution of 25% (volume/volume) to remove N in 4 times each 5 minutes ^α-Fmoc protecting group.Between each coupling, with NMP washing resin 6 times.With 85%TFA/5%TIS/5% thioanisole and 5% phenol polypeptide is downcut from resin, then by the cold Et of dry ice ₂O precipitates.Centrifugal and the freeze-drying with rough peptide is then by reversed-phase HPLC C ₁₈Post adopts the acetonitrile solution of 0.1%TFA and the aqueous solution of 0.1%TFA to come purified product to obtain the pure compound of white solid as moving phase.

Amino acid and N-hydroxybenzotriazole (HOBT) are dissolved among the NMP, and use HBTU or O-(7-nitrine benzo triazol-1-yl)-N according to sequence, N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) activates.For the HBTU activation, amino acid, HBTU are added with 10 equivalents with respect to resin extender, and NMM is added with 30 equivalents.Carry out twice HBTU activation, each two hours for each amino acid.For the HATU activation, amino acid, HATU are added with 10 equivalents with respect to resin extender, and diisopropyl ethyl amine (DIEA) is added with 20 equivalents.The HATU that carried out three hours for each amino acid activates.Use the piperidines nmp solution of 25% (volume/volume) to remove the Fmoc protecting group in 4 times each 5 minutes.Between each coupling, with NMP washing resin 6 times.With 85%TFA/5%TIS/5% thioanisole and 5% phenol polypeptide is downcut from resin, then by the cold Et of dry ice ₂O precipitates.Centrifugal and the freeze-drying with thick peptide is then by reversed-phase HPLC C ₁₈Post adopts the acetonitrile solution of 0.1%TFA and the aqueous solution of 0.1%TFA to come purified product to obtain the pure compound of white solid as moving phase.

Embodiment 2:HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS's (SEQ ID NO:2) is synthetic

The solid-phase polypeptide that uses the Fmoc chemistry to adopt the PL-Rink resin (0.68mmol/g, Polymer Laboratories) of Fmoc protection to carry out modified peptides on the Symphony Peptide synthesizer on the scale of 100mol synthesizes.In synthetic, used following N ^αThe amino acid of-Fmoc protection: Fmoc-Ser (tBu)-OH; Fmoc-Pro-OH; Fmoc-Ala-OH; Fmoc-Gly-OH; Fmoc; Fmoc-Asn (Trt)-OH; Fmoc-Lys (Boc)-OH; Fmoc-Leu-OH; Fmoc-Trp (Boc)-OH; Fmoc-Glu (tBu)-OH; Fmoc-Ile-OH; Fmoc-Phe-OH; Fmoc-Arg (Pbf)-OH; Fmoc-Val-OH; Fmoc-Met-OH; Fmoc-Gln (Trt)-OH; Fmoc-Asp (tBu)-OH; Fmoc-Thr (tBut)-OH and Fmoc-His (Trt)-OH.In brief, use 10 normal amino acid and 10 normal activator O-benzotriazole-1-base-N, N, N ¹, N ¹-tetramethyl-urea phosphofluoric acid ester (HBTU) or O-(7-nitrine benzo triazol-1-yl)-N, N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) and N-hydroxybenzotriazole (HOBT) carry out linked reaction in N-Methyl pyrrolidone (NMP).For the HBTU activation, amino acid, HBTU are added with 10 equivalents with respect to resin extender, and NMM is added with 30 equivalents.Carry out twice HBTU activation, each two hours for each amino acid.For the HATU activation, amino acid and HATU are added with 10 equivalents with respect to resin extender, and diisopropyl ethyl amine (DIEA) is added with 20 equivalents.The HATU that carried out three hours for each amino acid activates.Use the piperidines nmp solution of 25% (volume/volume) to remove N in 4 times each 5 minutes ^α-Fmoc protecting group.Between each coupling, with NMP washing resin 6 times.With 85%TFA/5%TIS/5% thioanisole and 5% phenol polypeptide is downcut from resin, then by the cold Et of dry ice ₂O precipitates.Centrifugal and the freeze-drying with thick peptide is then by reversed-phase HPLC C ₁₈Post adopts the acetonitrile solution of 0.1%TFA and the aqueous solution of 0.1%TFA to come purified product to obtain the pure compound of white solid as moving phase.

Embodiment 3:

Synthetic being provided among Figure 11.

Embodiment 4:

Synthetic being provided among Figure 12.

Embodiment 5:

Synthetic being provided among Figure 13.

Embodiment 6:

Synthetic being provided among Figure 14.

Embodiment 7:

Synthetic being provided among Figure 15.

Embodiment 8:

Synthetic being provided among Figure 16.

Embodiment 9:

Synthetic being provided among Figure 17.

Embodiment 10:

Synthetic being provided among Figure 18.

Embodiment 11:

Synthetic being provided among Figure 19.

Embodiment 12:

Synthetic being provided among Figure 20.

Embodiment 13:

Synthetic being provided among Figure 21.

Embodiment 14:

Synthetic being provided among Figure 22.

Embodiment 15:

Synthetic being provided among Figure 23.

Embodiment 16:

Synthetic being provided among Figure 24.Although this embodiment has used the compound of embodiment 11, the another kind of synthetic compound that also can in the first step, make full use of embodiment 12.In addition, although this embodiment has shown and being connected of N end, also can be with linking to each other on the free acid in

embodiment

11 and 12 compound left side and the peptide such as any nucleophilic side chains such as C, K, S, T or Y.Also as shown in this embodiment, the amino with the Fmoc protection on

embodiment

11 and 12 compound right side links to each other via amido linkage with the antibody recognition group G.

Embodiment 17:

Synthetic being provided among Figure 25.Although this embodiment has used the compound of embodiment 14, the another kind of synthetic compound that also can in the first step, make full use of embodiment 13 or 15.In addition, although being connected that this embodiment has shown and N holds, also can be with linking to each other on free acid on the left of the compound of embodiment 13～15 and the peptide such as any nucleophilic side chains such as C, K, S, T or Y.Also as shown in this embodiment, the free sour of compound right side with embodiment 13～15 links to each other via amido linkage with the antibody recognition group G.

Embodiment 18:

Synthetic being provided among Figure 26.Although this embodiment has used the compound of embodiment 11, the another kind of synthetic compound that also can in the first step, make full use of embodiment 12.

Embodiment 19:3-{2-[2-(2-{2-[2-(2-tert-butoxycarbonyl-oxyethyl group)-oxyethyl group]-oxyethyl group }-oxyethyl group)-oxyethyl group] oxyethyl group }-the propionic acid tert-butyl ester

Adopting, reported method (O.Seitz and H.Kunz, J.Org.Chem.62:813-826 (1997)) prepares title compound.One small pieces sodium Metal 99.5 is added four (ethylene glycol), and (47.5g also stirs in the solution in THF (200mL) 244mmol) and dissolves fully until sodium.(94g 730mmol) and in room temperature continues to stir 2 days to add tert-butyl acrylate then.(94g 730mmol) also continues to stir 2 days to add another part tert-butyl acrylate.With several 1N HCl neutralization reaction mixtures and concentrating under reduced pressure.Residue is suspended in the water also with ethyl acetate extraction (3 * 150mL).Organic layer after merging is used the salt water washing and drying on sodium sulfate.Thereby reduction vaporization falls volatile matter obtains the colourless liquid crude product, with this crude product silicagel column purifying (42g, 51%).

Embodiment 20:3-{2-[2-(2-{2-[2-(2-carbonyl-oxyethyl group)-oxyethyl group]-oxyethyl group }-oxyethyl group)-oxyethyl group]-oxyethyl group } propionic acid synthetic

With 3-{2-[2-(2-{2-[2-(2-tert-butoxycarbonyl-oxyethyl group)-oxyethyl group]-oxyethyl group-oxyethyl group)-oxyethyl group] oxyethyl group-(6g, 18.6mmol) solution in methyl-phenoxide (20mL) cools off in ice bath and adds trifluoroacetic acid (65g) the propionic acid tert-butyl ester.Reduce pressure after 3 hours in room temperature and to remove volatile matter and residue partition between the sodium hydrogen carbonate solution of ethyl acetate (50mL) and 5%.With 1N HCl acidifying water layer, with the saturated ethyl acetate extraction (3 * 50mL) of using then of NaCl.Organic layer after merging is used the salt water washing and drying on sodium sulfate.Thereby decompression is removed volatile matter and is obtained colorless liquid product (3.8g, 82%), and this product solidifies when refrigeration.

Embodiment 21:3-(2-{2-[2-(2-{2-[2-(4-{2-[2-(2-methyl-[1; 3] dioxolane-2-ylmethyl)-[1,3] dioxolane-2-yl]-and-the phenylamino formyl radical)-oxyethyl group]-oxyethyl group }-oxyethyl group)-oxyethyl group]-oxyethyl group }-oxyethyl group)-propionic acid synthetic

Will be from the compound (0.6g of embodiment 20,1.8mmol) be dissolved in the methylene dichloride (10mL), at room temperature add 4-{2-[2-(2-methyl-[1 then, 3] dioxolane-2-ylmethyl)-[1,3] dioxolane-2-yl]-ethyl }-aniline (0.3g, 1.4mmol) and add subsequently EDCI (0.28g, 1.8mmol).Wash RM after 1 hour with water and drying on sodium sulfate in room temperature.Thereby evaporate volatile matter and on silicagel column the dichloromethane solution purifying with 1%～15% methyl alcohol obtain gelationus title compound (0.47g, 32%).

Embodiment 22:4-{2-[2-(2-methyl-[1,3] dioxolane-2-ylmethyl)-[1,3] dioxolane-2-yl]-ethyl }-aniline synthetic

Fill in the clean flask of oven drying with 6-(4-nitrophenyl)-hexane-2, (3.7g 15.72mmol), then adds dry CH to the 4-diketone in this flask ₂Cl ₂(20mL) and add two TMS ethylene glycol subsequently (38.5mL 157.3mL), is cooled to gained solution-5 ℃ and stir then under argon gas.In reaction mixture, add TMSOTf (300 μ L) and solution was stirred 6 hours at-5 ℃.With pyridine (10ml) termination reaction and be poured into saturated NaHCO ₃In.Extract mixture with EtOAc, then with organic layer water and salt water washing, dry and concentrated to obtain yellow solid.Thereby with hexane this solid is ground and to obtain free-pouring light yellow solid (3.5g, 72%), be dissolved in it among EtOAc (50mL) and on the Parr rocker hydrogen-pressure with 50psi carry out hydrogenation.Relief reaction in two hours is filtered by the diatomite plate, uses CH ₂Cl ₂/ MeOH washs the diatomite plate up hill and dale, obtains oily title compound (1.46g, 100%) thereby the organic phase after will merging then is concentrated, and this compound solidifies when leaving standstill.

Embodiment 23A:4-[4-(3,5-dioxo hexyl)-phenylamino formyl radical]-butyric acid 2,5-dioxo tetramethyleneimine-1-base ester (10) synthetic

Step 1:6-(4-nitrophenyl)-hexane-2,4-diketone (11)

In reaction vessel (heat also vacuum-drying and have magnetic and stir magneton), add tetrahydrofuran (THF) and LDA (2M heptane/ethylbenzene/tetrahydrofuran (THF); 69.4mL, 138.9mmol).Solution is cooled to-78 ℃.Dropwise add heptane-2, the 4-diketone (7.13mL, 69.4mmol) and at-78 ℃ with solution stirring 30 minutes.(15.0g 69.4mmol) adds with portion with 4-nitrobenzyl bromine.Remove solution from dry ice/acetone batch, allow it be warming up to room temperature and stirred 16 hours.Solution is cooled to about 0 ℃ also uses 1M HCl termination reaction.Tetrahydrofuran (THF) is removed in decompression.Roughage is absorbed in the methylene dichloride also with 1M HCl and salt water washing.Wash water layer once more with methylene dichloride.With the dichloromethane layer drying (Na after merging ₂SO ₄) also reduce pressure and remove methylene dichloride.Ethyl acetate/hexane with 5%～15% is carried out gradient flash column chromatography (FCC) thereby is obtained title compound (8.5g, 52%; Yellow solid). ¹H?NMR(CDCl ₃)：δ8.14(d，J＝9.0Hz，2H)，δ7.43(d，J＝8.4Hz，2H)，δ5.45(s，1H)，δ3.06(t，J＝7.5Hz，2H)，δ2.64(t，J＝7.8Hz，2H)，δ2.04(s，3H)。

Step 2:4-[4-(3,5-dioxo hexyl)-phenylamino formyl radical]-butyric acid (12)

In reaction vessel, add 200mL tetrahydrofuran (THF), 6-(4-nitrophenyl)-hexane-2, and the 4-diketone (8.0g, 34.0mmol) and dihydropyrane-2, the 6-diketone (3.88g, 34.0mmol).With argon purge reaction vessel three times.Add about 200mg palladium (10 weight % in the gac).Import excess hydrogen with the argon purge reaction vessel and through balloon once more.With solution stirring at room 16 hours.Decompression is removed hydrogen and is removed catalyzer by filtering through diatomite.Thereby decompression is removed tetrahydrofuran (THF) and is obtained title compound (10.5g, 97%, yellow solid).

Step 3:4-[4-(3,5-dioxo hexyl)-phenylamino formyl radical]-butyric acid 2,5-dioxo tetramethyleneimine-1-base ester (10)

In reaction vessel (heat also vacuum-drying and have magnetic and stir magneton), add 4-[4-(3; 5-dioxo hexyl)-the phenylamino formyl radical]-butyric acid (10.53g; 33.0mmol), N-hydroxy-succinamide (3.8g; 33.0mmol) and 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (6.3g, 33.0mmol) and methylene dichloride (250mL).Solution stirred under room temperature nitrogen used citric acid, salt water washing and dry (Na in 16 hours then ₂SO ₄).Methylene dichloride is removed in decompression.The FCC of the ethyl acetate/hexane with 70% obtains title compound (7.4g, yellow solid, 54%). ¹H NMR (CDCl ₃): δ 7.87 (s, 1H), δ 7.43 (d, J=8.4Hz, 2H), δ 7.12 (d, J=8.4Hz, 2H), δ 5.46 (s, 1H), δ 2.89 (t (﹠amp; M), J=8.1Hz (to t), 7H), δ 2.73 (t, J=6.0Hz, 2H), δ 2.56 (t, J=7.2Hz, 2H), δ 2.47 (t, J=6.9Hz, 2H), δ 2.21 (p, J=6.6Hz, 2H), δ 2.04 (s, 3H).

Embodiment 23B:3-{2-[2-(2-{4-[4-(3,5-dioxo hexyl)-phenylamino formyl radical]-butyrylamino }-oxyethyl group)-oxyethyl group]-oxyethyl group }-propionic acid 2,5-dioxo-tetramethyleneimine-1-base ester (20) synthetic

Step 1:3-{2-[2-(2-hydroxyl-oxethyl)-oxyethyl group]-oxyethyl group }-the propionic acid tert-butyl ester

With the tert-butyl acrylate of metal Na (catalytic) in 0 ℃ add to be stirred (6.7mL, 46mmol) and 2-[2-(2-hydroxyl-oxethyl)-oxyethyl group]-(20.7g's ethanol 138mmol) spends the night in the solution in THF (100mL) and with this mixture stirring.Removing desolvates and will remain oily matter is dissolved among the EtOAc (100mL).Organic layer is washed with water (3 * 50mL) and at Na ₂SO ₄Thereby the last dry oily matter that obtains except that desolvating in a vacuum then corresponding to title compound, described oily matter will be directly used in next step.(M+1)＝279。

Step 2:3-{2-[2-(2-p-toluenesulfonyl sulfonyloxy-oxyethyl group)-oxyethyl group]-oxyethyl group }-the propionic acid tert-butyl ester

With Tosyl chloride (22.3g, 117mmol) by 3-{2-[2-(2-the hydroxyl-oxethyl)-oxyethyl group in stirring part adding]-oxyethyl group }-(16.3g's propionic acid tert-butyl ester 58.6mmol) and in the solution of 60mL pyridine in (240mL) and with this mixture stirring spends the night.Water (300mL) termination reaction is also isolated organic layer.Use CH ₂Cl ₂Aqueous layer extracted (2 * 100mL).With the organic layer after merging with HCl (1N, 100mL) and water (100mL) washs and at Na ₂SO ₄Last dry, obtain oily matter thereby remove in a vacuum then to desolvate corresponding to title compound, described oily matter will be directly used in next step.(M+1)＝433。

Step 3:3-{2-[2-(2-amino ethoxy)-oxyethyl group]-oxyethyl group }-the propionic acid tert-butyl ester

With NaN ₃(35g, 3-{2-[2-(2-p-toluenesulfonyl sulfonyloxy-oxyethyl group)-oxyethyl group during 538mmol) adding is stirred]-oxyethyl group }-(20g also will react to stir in DMF 46mmol) (150mL) solution and spend the night the propionic acid tert-butyl ester.To react water (200mL) dilution and (4 * 100mL) extract with EtOAc.With the washing of organic layer water (100mL) and salt solution (100mL) and at Na ₂SO ₄Last dry.Thereby remove to desolvate in a vacuum and obtain oily matter.Adopt the column chromatography of EtOAc/Hex (1: 4) to obtain corresponding to 3-{2-[2-(2-azido-oxyethyl group)-oxyethyl group]-oxyethyl group }-oily matter of the propionic acid tert-butyl ester, (M+1)=304.With Pd (on the carbon 5%) in EtOAc under hydrogen (1atm.) to this oily matter hydrogenation 3 days.Obtain oily matter thereby remove by filter catalyzer and remove in a vacuum to desolvate, (M+1)=278 corresponding to title compound.

Step 4:3-{2-[2-(2-{4-[4-(3,5-dioxo hexyl)-phenylamino formyl radical]-butyrylamino }-oxyethyl group)-oxyethyl group]-oxyethyl group } the propionic acid tert-butyl ester

With 4-[4-(3; 5-dioxo hexyl)-the phenylamino formyl radical]-butyric acid 2,5-dioxo tetramethyleneimine-1-base ester (1.5g, 3.6mmol), 3-{2-[2-(2-amino ethoxy)-oxyethyl group]-oxyethyl group-the propionic acid tert-butyl ester (1.0g; 3.6mmol) and DIEA (1.3 μ L are 7.2mmol) at CH ₂Cl ₂Solution (10mL) is in stirred overnight at room temperature.Obtain transparent oily title compound thereby removing in a vacuum desolvates and with the column chromatography that adopts EtOAc/MeOH residual oily matter is carried out purifying, (M+1)=579.

Step 5:3-{2-[2-(2-{4-[4-(3,5-dioxo hexyl)-phenylamino formyl radical]-butyrylamino }-oxyethyl group)-oxyethyl group]-oxyethyl group }-propionic acid 2,5-dioxo tetramethyleneimine-1-base ester

With 3-{2-[2-(2-{4-[4-(3,5-dioxo hexyl)-phenylamino formyl radical]-butyrylamino-oxyethyl group)-oxyethyl group]-oxyethyl group-(400mg 0.692mmol) is dissolved in TFA/CH to the propionic acid tert-butyl ester ₂Cl ₂(1: 1,3mL) in and this mixture stirred spends the night.Obtain oily matter thereby removing desolvates as sour intermediate.With this oily matter be dissolved in contain DIEA (569L, 3.09mmol), N-hydroxy-succinamide (119mg, 1.03mmol) and EDC (197mg, CH 1.0mmol) ₂Cl ₂Stir (4mL) and with this mixture and spend the night.Remove desolvate and with employing EtOAc/MeOH (95: 5) thus column chromatography residual oily matter carried out purifying obtain the oily title compound, (M+1)=620.

Embodiment 24: synthetic based on the GA target compound of h38c2

Can embodiment 16 be linked to each other with h38c2 with 17 compound by following process: 1mL antibody h38c2 is added in the stock solution of 10mg/mL target compound of 12 μ L at phosphate buffered saline buffer (10mg/mL), and before use the gained mixture was kept 2 hours in room temperature.

Embodiment 25

C.Rader, etc., J.Mol.Biol.332:889-899 (2003) describes the method for a kind of h38c2 of preparation in detail.Below the result in this reference, material and method are elaborated.

The result

Humanization is with people V _κGene DPK-9 and people J _κGene JK4 is used as the humanized framework in kappa light chain variable territory, and with people V _HGene DP-47 and people J _HGene J _H4 are used as the humanized framework of the heavy chain variable domain of m38C2.To be transplanted to people's class framework from m38C2 by all complementary determining regions (CDR) residue of definition such as Kabat and the framework residue of determining in light chain variable territory and heavy chain variable domain.The selection of the framework residue of transplanting is based on the crystalline structure of mouse mAb33F12Fab (PDB 1AXT).MAb 33F12Fab and m38c2 share 92% sequence homology and identical CDR length in variable domain.In addition, 33F12 has similar catalytic activity with m38C2.The residue that may participate in the catalytic activity of m38C2 is directly or indirectly formed and comprised to the framework residue of grafting by 5 residues in the light chain and 7 residues in the heavy chain.These residues comprise the reactive Methionin (Lys of the framework region that is positioned at heavy chain 3 (FR3) of m38C2 ^H93).6 conservative property residue Ser between mouse mAb 33F12 and the mouse mAb 38C2 ^H35, Val ^H37, Trp ^H47, Trp ^H103And Phe ^L98Be in Lys ^H93ε amino

Within the radius.These residues also are retained in humanization.Lys ^H93Be positioned at the bottom of the hydrophobic substrate binding site of height of mouse mAb 33F12 and mouse mAb 38C2.Except that the CDR residue, many framework residues are lining in this pocket.Wherein, Leu ^L37, Gln ^L42, Ser ^L43, Val ^L85, Phe ^L87, Val ^H5, Ser ^H40, Glu ^H42, Gly ^H88, Ile ^H89And Thr ^H94Be transplanted in people's class framework.

Express and pass through humanization variable domain and human constant domain C _κAnd C _{γ 1}1 fusion has at first produced as Fab and has been expressed in h38C2 in the intestinal bacteria.Then, be used for the PIGG carrier that IgG 1 expresses at mammalian cell with through engineering approaches and formed h38c2IgG from h38c2Fab.Allow supernatant liquor from the people 293T cell of transient transfection by affinity chromatography purifying on recombinant protein A, thereby generate about 1mg/L h38C2IgG1.Follow Coomassie blue stain by SDS-PAGE and determine purity.

Beta-diketone compound---

Beta-diketone compound---covalency by beta-diketon and m38c2 adds the enamine ketone that is shaped as at λ _Max=318nm place has the characteristic uv-absorbing.Similar to m38C2IgG, h38C2IgG with the beta-diketon incubation after demonstrate distinctive enamine ketone and absorb.As negative contrast, have the IgG1 isotype identical with h38C2 but not with the recombinant human anti-HIV-1 gp120mAb b12 of reactive Methionin with beta-diketon 2 incubations after do not demonstrate enamine ketone and absorb.Bonded for beta-diketon and m38C2 and h38C2 quantitatively contrasts, and the author has adopted competitive ELISA.With the beta-

diketon

2 and 3 incubations of antibody and progressive concentration and resist immobilized BSA-coupling beta-diketon 1 and test.The apparent equilibrium dissociation constant is 38 μ M (m38C2) and 7.6 μ M (h38C2) to beta-diketon 2, and is 0.43 μ M (m38C2) and 1.0 μ M (h38C2) to beta-diketon 3, demonstrate beta-diketon to mouse antibodies similar with humanized antibody in conjunction with character.

Material and method

Molecular simulation---made up the molecular model of h38C2Fab as template with relevant zymohexase antibody mouse 33F12Fab (Protein Data Bank ID:1AXT) by the homology simulation.Exist before this

Resolving power under determined the crystalline structure of mouse 33F12Fab. ⁴With the HOMOLOGY module of INSIGHT II software (Accelrys) comparison of mouse 33F12 and 38C2 aminoacid sequence two sequence height homologies have been confirmed.Their differences each other are in 226 amino acid of two variable domains 19 differences to be arranged, and their CDR shares identical length.Except the height sequence homology, to observe from the low resolution crystalline structure of 38C2, two structures all show considerable structural similarity, and the sudden change of the residue in the model is placed side chain with the aminoacid sequence that meets h38C2 and based on the standard rotational isomer.Adopt the first steepest descent of respectively doing for oneself of 100 steps to minimize then that the minimized step of conjugate gradient minimizes this model with the DISCOVER module among the INSIGHTII then.

The structure of h38C2 Fab---with variable light chain territory and the sequence in variable heavy chain territory and sequence (the V BASE that ethnic group is sequence D PK-9, JK4, DP-47 and JH4 of m38C2; See the internet, mrc-cpe.cam.ac.uk/vbase) design and be respectively applied for humanization V _κAnd V _HThe overlapping oligonucleotide of synthetic assembly.N-glycosylation site and internal limitations site HindIII, Xbal, SacI, ApaI and the SfiI of sequence NXS/T have been avoided having.Use expansion high-fidelity PCR system (Expand High Fidelity PCR System (Roche Molecular Systems)) to carry out PCR.Humanized V _κOligonucleotide is: L synonym flank (flank sense) (C.Rader etc., J.Biol.Chem.275:13668-13676 (2000)); H38C2L1 (synonym; 5 '-GAGCTCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGTGACCGCGT CACCATCACTTG-3 ') (SEQ.ID.NO:85); H38C2L2 (antisense; 5 '-ATTCAGATATGGGCTGCCATAAGTGTGCAGGAGGCTCTGACTGGAGCGGCAAGTGA TGGTGACGCGGTC-3 ') (SEQ.ID.NO:86); H38C2L3 (synonym; 5 '-TATGGCAGCCCATATCTGAATTGGTATCTCCAGAAACCAGGCCAGTCTCCTAAGCT CCTGATCTAT-3 ') (SEQ.ID.NO:87); H38C2L4 (antisense; 5 '-CTGAAACGTGATGGGACACCACTGAAACGATTGGACACTTTATAGATCAGGAGCTT AGGAGACTG-3 ') (SEQ.ID.NO:88); H38C2L5 (synonym; 5 '-AGTGGTGTCCCATCACGTTTCAGTGGCAGTGGTTCTGGCACAGATTTCACTCTCAC CATCAGCAGTCTGCAACCTGAAGATTTTGCAGTG-3 ') (SEQ.ID.NO:89); H38C2L6 (antisense; 5 '-GATCTCCACCTTGGTCCCTCCGCCGAAAGTATAAGGGAGGTGGGTGCCCTGACTAC AGAAGTACACTGCAAAATCTTCAGGTTGCAG-3 ') (SEQ.ID.NO:90) and L antisense flank (antisense flank) (C.Rader etc., J.Biol.Chem.275:13668-13676 (2000)).Humanized V _HOligonucleotide is: H synonym flank (C.Rader etc., J.Biol.Chem.275:13668-13676 (2000)); H38C2H1 (synonym; 5 '-GAGGTGCAGCTGGTGGAGTCTGGCGGTGGCTTGGTACAGCCTGGCGGTTCCCTGCG CCTCTCCTGTGCAGCCTCTGGCT-3 ') (SEQ.ID.NO:91); H38C2H2 (antisense; 5 '-CTCCAGGCCCTTCTCTGGAGACTGGCGGACCCAGCTCATCCAATAGTTGCTAAAGG TGAAGCCAGAGGCTGCACAGGAGAG-3 ') (SEQ.ID.NO:92); H38C2H3 (synonym; 5 '-TCTCCAGAGAAGGGCCTGGAGTGGGTCTCAGAGATTCGTCTGCGCAGTGACAACTA CGCCACGCACTATGCAGAGTCTGTC-3 ') (SEQ.ID.NO:93); H38C2H4 (antisense; 5 '-CAGATACAGCGTGTTCTTGGAATTGTCACGGGAGATGGTGAAGCGGCCCTTGACAG ACTCTGCATAGTGCGTG-3 ') (SEQ.ID.NO:94); H38C2H5 (synonym; 5 '-CAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCGCGCCGAGGACACGG GCATTTATTACTGTAAAACG-3 ') (SEQ.ID.NO:95); H38C2H6 (antisense; 5 '-TGAGGAGACGGTGACCAGGGTGCCCTGGCCCCAGTAGCTGAAACTGTAGAAGTACG TTTTACAGTAATAAATGCCCGTG-3 ') (SEQ.ID.NO:96); H antisense flank (C.Rader etc., J.Biol.Chem.275:13668-13676 (2000)).After assembling, with humanization V _κAnd V _HRespectively with people C _κAnd C _{γ 1}1 merges, and with the gained light chain and heavy chain fragment merges and as " C.Rader et al, J.Biol.Chem.275:13668-13676 (2000); C.F.Barbas 3 ^RdDeng, Phage Display:A laboratorymanual, Cold Spring Harbor Laboratory, Cold Spring Harbor N.Y. (2001) " described SfiI is cloned in the phagemid carrier pComb3X.For enrichment has the clone body of correct h38C2 sequence, Fab is illustrated on the phage and takes turns anti-immobilizedly select with elutriation BSA link coupled beta-diketon i (JW) by one.Produced solubility Fab and it has been used and horseradish peroxidase (Jackson ImmunoResearch Laboratories) the anti-people F of link coupled donkey (ab ') with combining by ELISA of immobilized JW-BSA from the monospecific polyclonal body ₂Polyclonal antibody resists as two to be tested.(C.F.Barbas 3 to adopt primer OMPSEQ and PELSEQ to analyze the light chain of positive clone body and heavy chain encoding sequence respectively by dna sequencing ^RdDeng, Phage Display:A laboratory manual, Cold Spring Harbor Laboratory, ColdSpring Harbor N.Y., (2001)) so that determine the V of h38C2 _κAnd V _HThe assembling sequence.

The structure of h38C2 IgG1, generation and purifying---the carrier PIGG (C.Rader et al, FASEB J., 16:2000-2002 (2002)) that will describe recently is used for the Mammals expression of h38C2IgG1.Mammalian expression vector PIGG-h38c2 as shown in figure 23.This 9kb carrier comprises heavy chain γ 1 and the light chain κ expression cassette that is driven by two-way CM promoter construct.Use primer PIGG-h38C2H (synonym; 5 '-GAGGAGGAGGAGGAGGAGCTCACTCCGAGGTGCAGCTGGTGGAGTCTG-3 ') (SEQ.ID.NO:97) and GBACK (C.F.Barbas 3 ^RdDeng, PhageDisplay:A laboratory manual, Cold Spring Harbor Laboratory, ColdSpring Harbor N.Y. (2001)) will be from the V of the h38C2Fab among the phagemid carrier pComb3X _HThe encoding sequence amplification with SacI and ApaI digestion, and is cloned in the carrier PIGG of suitable digestion.Use primer PIGG-h38C2L (synonym; 5 '-GAGGAGGAGGAGGAGAAGCTTGTTGCTCTGGATCTCTGGTGCCTACGGGGAGCTCC AGATGACCCAGTCTCC-3 ') (SEQ.ID.NO:98) and LEADB (C.F.Barbas 3 ^RdDeng, Phage Display:A laboratory manual, ColdSpring Harbor Laboratory, Cold Spring Harbor N.Y. (2001)) will be from the V of the h38C2Fab among the phagemid carrier pComb3X _LThe encoding sequence amplification with HindIII and XbaI digestion, and is cloned among the carrier PIGG of the suitable digestion of warp that contains the h38C2 heavy chain.With intermediate with final PIGG vector construction body increases among coli strain SURE (Stratagene) and extract test kit (Plasmid Maxi Kit) in a large number with qiagen plasmid prepares.From the preparation final PIGG vector construction body by generating h38C2IgG1 with Lipofectamine 2000 (Invitrogen) transient transfection people 293T cell.To keep for 2 weeks among GIBCO 10% ultralow IgG (＜0.1%) FCS (Invitrogen) of transfectional cell in RPMI 1640 (Hyclone).During this period, collect substratum and replacing three times.The substratum of collecting is gone up purifying by affinity chromatography at recombinant protein A HiTrap post (Amersham Biosciences).This purification step has generated 2.45mg h38C2IgG1 from 2 in the substratum that 300mL collects, and this output is by determining with the optical density (OD) at the biological spectrophotometric determination 280nm of Eppendorf place.In Slide-A-Lyzer 10K dialysis cassette (Pierce),, use Ultrafree-15 centrifugal filter (UFV2BTK40 with after the PBS dialysis; Millipore) antibody is concentrated into 760 μ g/mL, carries out sterile filtration by 0.2-μ m Acrodisc 13MM S-200 needle-based strainer (Pall) then.Ultimate capacity is 2.13mg (87%).Continue by irreducibility SDS-PAGE and to have confirmed the h38C2IgG1 of purifying with Coomassie blue stain.

The formation of enamine ketone---with antibody (h38C2IgG1 or b12IgG1) add beta-diketon (ii) in the antibody combining site concentration that reaches 25 μ M and the beta-diketon concentration of 125 μ M.Used SOFTmax Pro software (version 3 .1.2) to read plate device (Molecular Devices) in 10 minutes then at the room temperature incubation in this mixture and go up the collection UV spectrum at SpectraMax Plus 384UV.

In conjunction with test---unless indicate in addition, all solution all are phosphate buffered saline buffer (pH7.4).With beta-diketon (ii) or 2 * solution (iii) (50 μ L) add in the 50 μ L antibody (h38C2 or m38C2) and be allowed to condition at 37 ℃ of incubations 1 hour.Solution is mixed by pipettor.The ultimate density of antibody is the antibody combining site of 0.4nM～8nM, and beta-diketon (ii) and ultimate density (iii) be respectively 10 ^-9～10 ^-2M and 10 ^-10～10 ^-4M.Be coated with the TBS solution of the BSA conjugate of the beta-diketon (i) of 100ng each hole Costar 3,690 96 orifice plates (Corning).Add 50 μ L antibody/beta-diketon mixtures then, then add 50 goat-anti people Fc IgG polyclonal antibodies μ L and horseradish peroxidase (Pierce) or the anti-mouse Fc of rabbit IgG polyclonal antibody (Jackson ImmunoResearch Laboratories) 1: 1,000 diluent.Add 50 μ L ABTS substrate solutions subsequently.Between each the adding, plate built and, spend IONS OF H then 37 ℃ of incubations 1 hour ₂O washing 5 times.The absorbancy of monitoring the 405nm place as mentioned above reaches appropriate value (0.5＜A up to the reaction that does not have beta-diketon ₄₀₅＜1.0).For each hole, the fraction that calculates the ELISA signal with equation (a) suppresses (fractional inhibition):

v _i＝(A _o-A _i)/(A _o) (a)

A wherein _oBe the ELISA absorbancy that when beta-diketon does not exist, obtains, and A _oIt is the ELISA absorbancy that when beta-diketon exists, obtains.For monovalent conjugated protein, with solubility beta-diketon (f _i) component of bonded antibody equals v _iYet IgG antibody is divalence, and the ELISA signal only be subjected to two coordinate antibody existence inhibition and not suppressed by the unit price bonded.Therefore, used Stevens to proofread and correct to bivalent antibody,

f _i＝(v _i) ^1/2 (b)

Used following relation to determine the apparent equilibrium dissociation constant:

f _i＝f _min+(f _max-f _min)(1+K _D/a ₀) ^-1 (c)

A wherein ₀Corresponding to the total concn of beta-diketon, K _DBe equilibrium dissociation constant, and f _MinAnd f _MaxRepresent the experiment determined value when antibody combining site is not occupied or be saturated respectively.Because this equation is only at K _DValue is effective during than high at least 10 times of antibody concentration, has confirmed the K that determines from equation iii _DValue has reached this standard.The nonlinear least square fitting method of using KaleidaGraph (version 3 .0.5, Abelbeck software) is with K _D, f _MaxAnd f _MinCome data are carried out match and used equation (d) normalization method as adjustable parameter:

f _norm＝(f _i-f _min)/(f _max-f _min) (d)

Synthesizing of embodiment 26:20 atom A ZD maleimide joint

Be provided among Figure 29.

Embodiment 27:

Among synthetic Figure 30 of being provided in of the Lys that the side chain that can together use with joint shown in Figure 29 is modified.

Embodiment 28:

The synthetic of GA target agent-joint conjugate is provided in Fig. 3 l, and this GA target agent-joint conjugate comprises the GA target peptide of the SEQ ID NO:22 that the Lys residue modified via the side chain in the peptide links to each other with 20 atom A ZD maleimide joints shown in Figure 29.

Embodiment 29:

The synthetic of GA target agent-joint conjugate is provided in Figure 32, and this GA target agent-joint conjugate comprises the GA target peptide of the SEQ ID NO:32 that the Lys residue modified via the side chain in the peptide links to each other with 20 atom A ZD maleimide joints shown in Figure 29.

The sign of the external insulin secretion that embodiment 30:GA target is peptide-mediated

Generated with identical general method and to have had SEQ ID NO:1～the GA target peptide analogs of 76 aminoacid sequences of describing with the GA target peptide that is used for SEQ ID NO:1 and SEQ ID NO:2 described in

embodiment

1 and 2.

The insulin secretion (GSIS) that adopts glucose to stimulate is tested SEQ IDNO:1～13,32,35,40～47,49～51,53～55 and 57～63 GA target peptide in the ability of stimulated in vitro from the insulin secretion of pancreatic beta cell.In brief, glucose and GA target peptide are added in the pancreatic beta cell culture with different concns, detect insulin secretion by measuring the insulin level that carries out in time then.Each peptide is calculated EC50.This test result is listed in the table below among the III.

Table III

GA target peptide EC50 (μ M)

SEQ?ID?NO：1(GLP-17-36) ＜10

SEQ?ID?NO：2(exendin-4) ＜10

SEQ?ID?NO：3 ＜10

SEQ?ID?NO：4 ＜10

SEQ?ID?NO：5 ＜10

SEQ?ID?NO：6 ＜10

SEQ?ID?NO：7 ＜10

SEQ?ID?NO：8 ＜10

SEQ?ID?NO：9 ＜10

SEQ?ID?NO：10 ＜10

SEQ?ID?NO：11 ＜10

SEQ?ID?NO：12 ＜10

SEQ?ID?NO：13 ＜10

SEQ?ID?NO：32 ＜10

SEQ?ID?NO：35 ＜10

SEQ?ID?NO：40 ＜10

SEQ?ID?NO：41 ＜10

SEQ?ID?NO：42 ＜10

SEQ?ID?NO：43 ＜10

SEQ?ID?NO：44 ＜10

SEQ?ID?NO：45 ＜10

SEQ?ID?NO：46 ＜10

SEQ?ID?NO：47 ＜10

SEQ?ID?NO：49 ＜10

SEQ?ID?NO：50 ＜10

SEQ?ID?NO：51 ＜10

SEQ?ID?NO：53 ＜10

SEQ?ID?NO：54 ＜10

SEQ?ID?NO：55 ＜10

SEQ?ID?NO：57 ＜10

SEQ?ID?NO：58 ＜10

SEQ?ID?NO：59 ＜10

SEQ?ID?NO：60 ＜10

SEQ?ID?NO：61 ＜10

SEQ?ID?NO：62 ＜10

SEQ?ID?NO：63 ＜10

The sign of the external insulin secretion that embodiment 31:GA target peptide-joint is couplet mediated

The GA target peptide of SEQ ID NO:1～76 is connected to generate GA target peptide-joint conjugate with different joints.SEQ ID NO:3～5,14～33,35～37,57 are connected with synthetic 20 atom A ZD maleimide joints (" 20-atom A ZD ") among the embodiment 26 with 63～72 GA target peptide, and this joint has following structure:

For the ligation of the peptide of the GA target peptide of SEQ ID NO:22 and SEQ ID NO:32 and 20-atom A ZD respectively as shown in Figure 26 and Figure 27.

SEQ ID NO:32 is connected with 10-atom A ZD maleimide joint " 10-atom A ZD " with 37 GA target peptide, and this joint has following structure:

The GA target peptide of SEQ ID NO:37 is connected with 13-atom A ZD maleimide joint " 13-atom A ZD ", and this joint has following structure:

SEQ ID NO:35 is connected with 16-atom A ZD maleimide joint " 16-atom A ZD " with 37 GA target peptide, and this joint has following structure:

The GA target peptide of SEQ ID NO:35 is connected with 26-atom A ZD maleimide joint " 26-atom A ZD ", and this joint has following structure:

SEQ ID NO:33 is connected with joint " Gly-AZD " with 37 GA target peptide, and this joint has following structure:

SEQ ID NO:1,33,34 is connected with joint " PEG4-Glu-DK joint " with 36～37 GA target peptide, and this joint has following structure:

Adopt embodiment 30 described GSIS tests that these GA target agent-joint conjugates are measured in the ability of stimulated in vitro insulin secretion.Those conjugates that use is made up of the GA target peptide of SEQ ID NOs:4-5 that links to each other with 20-atom A ZD and 14-31 are tied walking experiment (tethered walk experiment) to determine to be connected the optimum position of GA target peptide and joint.Each all contains the Lys residue that the side chain of with good grounds scheme shown in Figure 30 is modified these peptides in different positions.This experimental result is listed in the table below among the IV.

Figure IV

GA target agent-joint conjugate EC50 (μ M)

SEQ ID NO:4-20 atom A ZD＜10

SEQ ID NO:5-20 atom A ZD＜10

SEQ ID NO:19-20 atom A ZD＜10

SEQ ID NO:20-20 atom A ZD＜10

SEQ ID NO:21-20 atom A ZD＜10

SEQ ID NO:22-20 atom A ZD＜10

SEQ ID NO:23-20 atom A ZD＜10

SEQ ID NO:24-20 atom A ZD＜10

SEQ ID NO:25-20 atom A ZD＜10

SEQ ID NO:26-20 atom A ZD＜10

SEQ ID NO:27-20 atom A ZD＜10

SEQ ID NO:28-20 atom A ZD＜10

SEQ ID NO:32-20 atom A ZD＜10

SEQ ID NO:37-20 atom A ZD＜10

SEQ ID NO:32-10 atom A ZD＜10

SEQ ID NO:37-10 atom A ZD＜10

SEQ ID NO:35-26 atom A ZD＜10

SEQ?ID?NO：33-Gly-AZD ＜10

SEQ?ID?NO：1-PEG4-Glu-DK ＜10

SEQ?ID?NO：33-PEG4-Glu-DK ＜10

SEQ ID NO:34-PEG4-Glu-DK (connecting)＜10 through K20

SEQ ID NO:34-PEG4-Glu-DK (connecting)＜10 at the N end

SEQ?ID?NO：36-PEG4-G1u-DK ＜10

SEQ?ID?NO：37-PEG4-Glu-DK ＜10

SEQ ID NO:74 (linking to each other with the benzoyl end-blocking)＜10 through K28

SEQ ID NO:75 (with N end anti--3-is acetyl blocked to link to each other)＜10

SEQ ID NO:76 (with acetyl blocked the linking to each other of 3-aminophenyl of N end)＜10

Embodiment 32: glucose tolerance test (GTT), body weight change and food intake

Use the glucose tolerance test pattern (Figure 35) of single dose or repeated doses that drug effect in the body of exemplary GA target compound of the present invention and reagent is assessed.To young bull ob/ob mouse (Jackson Laboratories, Bar Harbor ME) adopts brief manually constraint (brief manual restraint.) to carry out subcutaneous (SC) administration with compound of the present invention with the volume injected of 0.2mL～0.3mL in middle omoplate district.With carrier (Vehicle) the brood cub of slight of stature is raiseeed control mice (n=8/ group, Jackson Laboratories, Bar Harbor, ME) similarly administration.Morning every day (08:00～09:00H; 06:00H turns on light, and 18:00H turns off the light) monitoring food intake (Figure 36) and accumulation body weight change (Figure 37).

Following standard scheme makes mouse stand oral glucose tolerance test (OGTT).In brief, with the fasting 4 hours～5 hours when the phase of turning on light begins of the mouse in the population.When this finishes in stage (afternoon is early stage), at interval mouse is got tail blood with 15 minutes～120 minutes rule before and thereafter imposing oral glucose load (1.5g/kg).Food returned in the cage and at 120 minutes collect behind the time point.Determine glucose level with the self-test blood glucose meter, and calculate as the area under curve (AUC) of the glucose of the function of time after to oral glucose load with linear trapezoidal equation.

Connection (SEQ ID NO:21) at 23 places, position did not reduce body weight or food ration and improved the glucose dosis tolerata in 48 hour.In the position 17,24,38 places with reduced body weight and food ration in being connected of C end (SEQ ID NO:25,20,14,131,132) but in 72 hours, do not improved the glucose dosis tolerata.Connection (SEQ ID NO:19) at 26 places, position did not reduce body weight or food ration but improved the glucose dosis tolerata in 48 hour.All examples adopt K or K (SH) as connecting residue., show good compound under certain conditions and may be suitable for some application aspect some of the present invention.Others at this aspect, the compound that shows advantage under a plurality of test conditions may be favourable.

Data are represented with mean+/-standard error and are tested back multiple comparisons (Dunnett ' s post-hoc test) by unidirectional ANOVA (GraphPad Prism 4.0 with Dunnett, GraphPad Software Inc., San Diego, CA) analysis bank differences.

The present invention is carried out the above-mentioned representative embodiments of open widely also reference thus and carried out the example explanation.Those skilled in the art will recognize that and to make various changes to the present invention not deviating under the spirit and scope of the present invention.Introduce all publications, patent application and publication by reference herein, its degree is introduced by reference each independent publication, patent application or publication as specifically and specifically having shown with integral body.By being left out with reference to the contained definition of introducing of text so that these definition are inconsistent with the definition in the disclosure.

Word " comprises/comprising " and word " having/including " are used for indicating the existence of feature, integral body, step or the composition of being stated but do not get rid of the existence or the interpolation of one or more features, integral body, step, composition or their group.

Be appreciated that to some feature of the present invention of describing in the context of the embodiment that separates for the purpose of distinct also can make up and be provided in the single embodiment.Otherwise, for the different characteristics of the present invention described in the context of single embodiment for the purpose of brief also can be respectively or close with any suitable subgroup and to provide.

As mentioned above, obviously can carry out various changes and variation effectively and do not deviate from the true spirit and the scope of novel concept of the present invention.Be appreciated that the disclosure is intended to state example of the present invention, these examples are not to be intended to limit the invention in the illustrated embodiment.The disclosure is intended to include all changes in the claim scope by appended claim.

When being with reference symbol behind the technical characterictic of mentioning in any claim, comprise that the purpose of these reference symbols only is to increase the clarity of this claim, so these reference symbols are without any the limiting effect of the scope of each element that the mode of being passed through example by these reference symbols is determined.

Sequence table

＜110〉the Irish company limited of Covx science and technology

＜120〉glucagon albumen-1 acceptor GLP-1R agonist compound

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<151>2007-01-05

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<170>PatentIn?version?3.4

<210>1

<211>30

<212>PRT

＜213〉homo sapiens

<400>1

His?Ala?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg

20 25 30

<210>2

<211>39

<212>PRT

＜213〉Monster

<400>2

His?Gly?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>3

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉has the Exendin-4 peptide that the C-end adds Methionin

<400>3

His?Gly?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?PheIle?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Lys

35 40

<210>4

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up that Gly is substituted by Aib2 and the C-end adds the Exendin-4 peptide of Methionin

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>4

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Lys

35 40

<210>5

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up Gly by Aib2 alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>5

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>6

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up that Gly are substituted by Aib2 and the Exendin-4 peptide of 9 amino acid carboxyls brachymemma

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>6

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly

20 25 30

<210>7

<211>28

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up that Gly are substituted by Aib2 and the Exendin-4 peptide of 11 amino acid carboxyls brachymemma

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>7

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?PheIle?Glu?Trp?Leu?Lys?Asn

20 25

<210>8

<211>28

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Gly by Aib2 substitute, 14 go up Met by Leu substitute, 25 go up that Trp is substituted by Phe and the Exendin-4 peptide of 11 amino acid carboxyls brachymemma

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>8

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Leu?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Phe?Leu?Lys?Asn

20 25

<210>9

<211>28

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Gly by Aib2 substitute, 14 go up Met by Leu substitute, 22 go up Phe by Ala substitute, 25 go up that Trp is substituted by Phe and the Exendin-4 peptide of 11 amino acid carboxyls brachymemma

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>9

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Leu?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Ala?Ile?Glu?Phe?Leu?Lys?Asn

20 25

<210>10

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Gly by Aib2 substitute, 14 go up Met by Leu substitute, 22 go up Phe by Ala substitute, 25 go up Trp by Phe alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>10

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Leu?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Ala?Ile?Glu?Phe?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>11

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Gly by Aib2 substitute, 14 go up that Met is substituted by Leu and 25 go up Trp by Phe alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>11

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Leu?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe Ile?Glu?Phe?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>12

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Gly by Aib2 substitute, 12 go up that K is substituted by K (Ac) and 27 go up K by K (Ac) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(12)..(12)

＜223〉Methionin (Ac)

<220>

<221>MISC_FEATURE

<222>(27)..(27)

＜223〉Methionin (Ac)

<400>12

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Xaa?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Xaa?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>13

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Gly by Aib2 substitute, 12 go up that K is substituted by K (benzoyl) and 27 go up K by K (benzoyl) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(12)..(12)

＜223〉Methionin (benzoyl)

<220>

<221>MISC_FEATURE

<222>(27)..(27)

＜223〉Methionin (benzoyl)

<400>13

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Xaa?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Xaa?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>14

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 38 go up Pro by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>14

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Lys?Ser

35

<210>15

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 36 go up Pro by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>15

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Lys?Pro?Pro?Ser

35

<210>16

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 34 go up Gly by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>16

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Lys?Ala?Pro?Pro?Pro?Ser

35

<210>17

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 32 go up Ser by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>17

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Lys

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>18

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 28 go up Asn by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>18

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Lys?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>19

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 26 go up Leu by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>19

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Lys?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>20

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 24 go up Glu by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>20

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Lys?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>21

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 23 go up Ile by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>21

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Lys?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>22

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 21 go up Leu by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>22

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Lys?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>23

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 20 go up Arg by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>23

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Lys?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>24

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 19 go up Val by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>24

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Lys?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>25

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 17 go up Glu by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>25

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Lys?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>26

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 16 go up Glu by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>26

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Lys

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>27

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 14 go up Met by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>27

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Lys?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>28

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 13 go up Gln by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>28

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Lys?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>29

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 11 go up Ser by Lys alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>29

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Lys?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>30

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Gly by Aib2 substitute, 31 go up that Pro is substituted by Lys and the Exendin-4 peptide of 8 amino acid carboxyls brachymemma

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>30

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Lys

20 25 30

<210>31

<211>33

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Gly by Aib2 substitute, 21 go up that Leu is substituted by Lys and the Exendin-4 peptide of 6 amino acid carboxyls brachymemma

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>31

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Lys?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser

<210>32

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up Ala by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>32

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg

20 25 30

<210>33

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉has GLP-1 (7-36) peptide that the C-end adds Methionin

<400>33

His?Ala?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Lys

20 25 30

<210>34

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up that Ala is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Methionin

<400>34

His?Gly?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Lys

20 25 30

<210>35

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Ala are substituted by Aib2 and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>35

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>36

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 29 go up that Gly is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Methionin

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>36

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg?Lys

20 25 30

<210>37

<211>31

<212>PRT

＜213〉artificial sequence

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>37

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Lys

20 25 30

<210>38

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up that Ala is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(31)

＜223〉Methionin (SH)

<400>38

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Xaa

20 25 30

<210>39

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Ala are substituted by Aib2 and 20 go up Lys by Lys (SH) alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin (SH)

<400>39

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Xaa?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg

20 25 30

<210>40

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up that Leu is substituted by Gly and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>40

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Gly?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>41

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up that Leu is substituted by Cys and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>41

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Cys?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>42

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up that Leu is substituted by Phe and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>42

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Phe?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>43

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up that Leu is substituted by Tyr and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>43

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Tyr?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>44

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up that Leu is substituted by Trp and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>44

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Trp?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>45

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up that Gly is substituted by Glu and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>45

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>46

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up that Gly is substituted by Asp and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>46

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Asp

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>47

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up that Gly is substituted by Lys and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>47

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Lys

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>48

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 19 go up that Ala is substituted by Val and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>48

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>49

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 19 go up that Ala is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>49

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ile?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>50

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 19 go up that Ala is substituted by Leu and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>50

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Leu?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>51

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 20 go up that Lys is substituted by Arg and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>51

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>52

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 20 go up that Lys is substituted by Orn and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉ornithine

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>52

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Xaa?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>53

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 25 go up that Trp is substituted by Phe and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>53

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?PheIle?Ala?Phe?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>54

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>54

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>55

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 28 go up that Lys is substituted by Arg and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>55

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Xaa?Arg

20 25 30

<210>56

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 28 go up that Lys is substituted by Orn and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(28)..(28)

＜223〉ornithine

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>56

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?PheIle?Ala?Trp?Leu?Val?Xaa?Xaa?Arg

20 25 30

<210>57

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>57

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>58

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up Leu by Phe substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>58

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Phe?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>59

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up Leu by Tyr substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>59

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val Ser?Ser?Tyr?Tyr?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>60

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up Leu by Trp substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>60

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Trp?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?PheIle?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>61

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up Val by Ile substitute, 28 go up that Lys is substituted by Arg and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>61

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?PheIle?Ala?Trp?LeuIle?Arg?Xaa?Arg

20 25 30

<210>62

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have respectively at 2,16,19,20,27,28 and 29 go up Ala by Aib2 substitute, Gly by Glu substitute, Ala by Val substitute, Lys by Arg, Val by Ile, Lys by Arg and Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>62

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Arg?Xaa?Arg

20 25 30

<210>63

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉GLP-1 (7-36)/exendin-4 fusogenic peptide

<220>

<221>MISC_FEATURE

<222>(1)..(30)

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(39)

＜223〉corresponding to the 31-39 residue of exendin-4

<400>63

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>64

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 10 go up Val by Lys substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>64

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Lys?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>65

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 12 go up Ser by Lys substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>65

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Lys?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>66

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up Leu by Lys substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>66

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Lys?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>67

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Lys substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>67

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Lys

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>68

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 18 go up Ala by Lys substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>68

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Lys?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>69

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 22 go up Phe by Lys substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>69

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Lys?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>70

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 24 go up Ala by Lys substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>70

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Lys?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>71

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 26 go up Leu by Lys substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>71

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Lys?Ile?Lys?Xaa?Arg

20 25 30

<210>72

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉GLP-1 (7-36)/exendin-4 fusogenic peptide

<220>

<221>MISC_FEATURE

<222>(1)..(30)

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(39)

＜223〉corresponding to the 31-39 residue of Exendin-4

<400>72

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Lys

35 40

<210>73

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up Val by Ile substitute, 28 go up that Lys is substituted by Lys (Ac) and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(28)..(28)

＜223〉Methionin (Ac)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>73

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Xaa?Xaa?Arg

20 25 30

<210>74

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up Val by Ile substitute, 28 go up that Lys is substituted by Lys (benzoyl) and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(28)..(28)

＜223〉Methionin (benzoyl)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>74

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Xaa?Xaa?Arg

20 25 30

<210>75

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have anti--3-caproyl of linking to each other by His residue and N-end, in 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 upward Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(1)..(1)

＜223〉with instead-Histidine that the 3-caproyl links to each other

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>75

Xaa?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>76

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have the 3-aminophenyl ethanoyl that links to each other with N-end His residue, in 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 upward Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(1)..(1)

＜223〉Histidine that links to each other with 3-aminophenyl ethanoyl

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>76

Xaa?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>77

<211>112

<212>PRT

＜213〉house mouse

<220>

<221>MISC_FEATURE

<222>(1)..(23)

<223>FR1

<220>

<221>MISC_FEATURE

<222>(24)..(39)

<223>CDR1

<220>

<221>MISC_FEATURE

<222>(40)..(54)

<223>FR2

<220>

<221>MISC_FEATURE

<222>(55)..(61)

<223>CDR2

<220>

<221>MISC_FEATURE

<222>(62)..(93)

<223>FR3

<220>

<221>MISC_FEATURE

<222>(94)..(102)

<223>CDR3

<220>

<221>MISC_FEATURE

<222>(103)..(112)

<223>FR4

<400>77

Asp?Val?Val?Met?Thr?Gln?Thr?Pro?Leu?Ser?Leu?Pro?Val?Arg?Leu?Gly

1 5 10 15

Asp?Gln?Ala?Ser?Ile?Ser?Cys?Arg?Ser?Ser?Gln?Ser?Leu?Leu?His?Thr

20 25 30

Tyr?Gly?Ser?Pro?Tyr?Leu?Asn?Trp?Tyr?Leu?Gln?Lys?Pro?Gly?Gln?Ser

35 40 45

Pro?Lys?Leu?Leu?Ile?Tyr?Lys?Val?Ser?Asn?Arg?Phe?Ser?Gly?Val?Pro

50 55 60

Asp?Arg?Phe?Ser?Gly?Ser?Gly?Ser?Gly?Thr?Asp?Phe?Thr?Leu?Arg?Ile

65 70 75 80

Ser?Arg?Val?Glu?Ala?Glu?Asp?Leu?Gly?Val?Tyr?Phe?Cys?Ser?Gln?Gly

85 90 95

Thr?His?Leu?Pro?Tyr?Thr?Phe?Gly?Gly?Gly?Thr?Lys?Leu?Glu?Ile?Lys

100 105 110

<210>78

<211>118

<212>PRT

＜213〉house mouse

<220>

<221>MISC_FEATURE

<222>(1)..(30)

<223>FR1

<220>

<221>MISC_FEATURE

<222>(31)..(35)

<223>CDR1

<220>

<221>MISC_FEATURE

<222>(36)..(49)

<223>FR2

<220>

<221>MISC_FEATURE

<222>(50)..(68)

<223>CDR2

<220>

<221>MISC_FEATURE

<222>(69)..(100)

<223>FR3

<220>

<221>MISC_FEATURE

<222>(101)..(107)

<223>CDR3

<220>

<221>MISC_FEATURE

<222>(108)..(118)

<223>FR4

<400>78

Glu?Val?Lys?Leu?Val?Glu?Ser?Gly?Gly?Gly?Leu?Val?Gln?Pro?Gly?Gly

1 5 10 15

Thr?Met?Lys?Leu?Ser?Cys?Glu?Ile?Ser?Gly?Leu?Thr?Phe?Arg?Asn?Tyr

20 25 30

Trp?Met?Ser?Trp?Val?Arg?Gln?Ser?Pro?Glu?Lys?Gly?Leu?Glu?Trp?Val

35 40 45

Ala?Glu?Ile?Arg?Leu?Arg?Ser?Asp?Asn?Tyr?Ala?Thr?His?Tyr?Ala?Glu

50 55 60

Ser?Val?Lys?Gly?Lys?Phe?Thr?Ile?Ser?Arg?Asp?Asp?Ser?Lys?Ser?Arg

65 70 75 80

Leu?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Arg?Thr?Glu?Asp?Thr?Gly?Ile?Tyr

85 90 95

Tyr?Cys?Lys?Thr?Tyr?Phe?Tyr?Ser?Phe?Ser?Tyr?Trp?Gly?Gln?Gly?Thr

100 105 110

Leu?Val?Thr?Val?Ser?Ala

115

<210>79

<211>112

<212>PRT

＜213〉homo sapiens

<220>

<221>MISC_FEATURE

<222>(1)..(23)

<223>FR1

<220>

<221>MISC_FEATURE

<222>(24)..(39)

<223>CDR1

<220>

<221>MISC_FEATURE

<222>(40)..(54)

<223>FR2

<220>

<221>MISC_FEATURE

<222>(55)..(61)

<223>CDR2

<220>

<221>MISC_FEATURE

<222>(62)..(93)

<223>FR3

<220>

<221>MISC_FEATURE

<222>(94)..(102)

<223>CDR3

<220>

<221>MISC_FEATURE

<222>(103)..(112)

<223>FR4

<400>79

Glu?Leu?Gln?Met?Thr?Gln?Ser?Pro?Ser?Ser?Leu?Ser?Ala?Ser?Val?Gly

1 5 10 15

Asp?Arg?Val?Thr?Ile?Thr?Cys?Arg?Ser?Ser?Gln?Ser?Leu?Leu?His?Thr

20 25 30

Tyr?Gly?Ser?Pro?Tyr?Leu?Asn?Trp?Tyr?Leu?Gln?Lys?Pro?Gly?Gln?Ser

35 40 45

Pro?Lys?Leu?Leu?Ile?Tyr?Lys?Val?Ser?Asn?Arg?Phe?Ser?Gly?Val?Pro

50 55 60

Ser?Arg?Phe?Ser?Gly?Ser?Gly?Ser?Gly?Thr?Asp?Phe?Thr?Leu?Thr?Ile

65 70 75 80

Ser?Ser?Leu?Gln?Pro?Glu?Asp?Phe?Ala?Val?Tyr?Phe?Cys?Ser?Gln?Gly

85 90 95

Thr?His?Leu?Pro?Tyr?Thr?Phe?Gly?Gly?Gly?Thr?Lys?Val?Glu?Ile?Lys

100 105 110

<210>80

<211>118

<212>PRT

＜213〉homo sapiens

<220>

<221>MISC_FEATURE

<222>(1)..(30)

<223>FR1

<220>

<221>MISC_FEATURE

<222>(31)..(35)

<223>CDR1

<220>

<221>MISC_FEATURE

<222>(36)..(49)

<223>FR2

<220>

<221>MISC_FEATURE

<222>(50)..(68)

<223>CDR2

<220>

<221>MISC_FEATURE

<222>(69)..(100)

<223>FR3

<220>

<221>MISC_FEATURE

<222>(101)..(107)

<223>CDR3

<220>

<221>MISC_FEATURE

<222>(108)..(118)

<223>FR4

<400>80

Glu?Val?Gln?Leu?Val?Glu?Ser?Gly?Gly?Gly?Leu?Val?Gln?Pro?Gly?Gly

1 5 10 15

Ser?Leu?Arg?Leu?Ser?Cys?Ala?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Asn?Tyr

20 25 30

Trp?Met?Ser?Trp?Val?Arg?Gln?Ser?Pro?Glu?Lys?Gly?Leu?Glu?Trp?Val

35 40 45

Ser?Glu?Ile?Arg?Leu?Arg?Ser?Asp?Asn?Tyr?Ala?Thr?His?Tyr?Ala?Glu

50 55 60

Ser?Val?Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asn?Ser?Lys?Asn?Thr

65 70 75 80

Leu?Tyr?Leu?Gln?Met?Asn?Ser?Leu?Arg?Ala?Glu?Asp?Thr?Gly?Ile?Tyr

85 90 95

Tyr?Cys?Lys?Thr?Tyr?Phe?Tyr?Ser?Phe?Ser?Tyr?Trp?Gly?Gln?Gly?Thr

100 105 110

Leu?Val?Thr?Val?Ser?Ser

115

<210>81

<211>95

<212>PRT

＜213〉homo sapiens

<220>

<221>MISC_FEATURE

<222>(1)..(23)

<223>FR1

<220>

<221>MISC_FEATURE

<222>(24)..(34)

<223>CDR1

<220>

<221>MISC_FEATURE

<222>(35)..(49)

<223>FR2

<220>

<221>MISC_FEATURE

<222>(50)..(56)

<223>CDR2

<220>

<221>MISC_FEATURE

<222>(57)..(88)

<223>FR3

<220>

<221>MISC_FEATURE

<222>(89)..(95)

<223>CDR3

<400>81

Asp?Ile?Gln?Met?Thr?Gln?Ser?Pro?Ser?Ser?Leu?Ser?Ala?Ser?Val?Gly

1 5 10 15

Asp?Arg?Val?Thr?Ile?Thr?Cys?Arg?Ala?Ser?Gln?Ser?Ile?Ser?Ser?Tyr

20 25 30

Leu?Asn?Trp?Tyr?Gln?Gln?Lys?Pro?Gly?Lys?Ala?Pro?Lys?Leu?Leu?Ile

35 40 45

Tyr?Ala?Ala?Ser?Ser?LeuGln?Ser?Gly?Val Pro?Ser?Arg?Phe?Ser?Gly

50 55 60

Ser?Gly?Ser?Gly?Thr?Asp?Phe?Thr?Leu?Thr?Ile?Ser?Ser?Leu?Gln?Pro

65 70 75 80

Glu?Asp?Phe?Ala?Thr?Tyr?Tyr?Cys?Gln?Gln?Ser?Tyr?Ser?Thr?Pro

85 90 95

<210>82

<211>98

<212>PRT

＜213〉homo sapiens

<220>

<221>MISC_FEATURE

<222>(1)..(30)

<223>FR1

<220>

<221>MISC_FEATURE

<222>(31)..(35)

<223>CDR1

<220>

<221>MISC_FEATURE

<222>(36)..(49)

<223>FR2

<220>

<221>MISC_FEATURE

<222>(50)..(66)

<223>CDR2

<220>

<221>MISC_FEATURE

<222>(67)..(98)

<223>FR3

<400>82

Glu?Val?Gln?Leu?Leu?Glu?Ser?Gly?Gly?Gly?Leu?Val?Gln?Pro?Gly?Gly

1 5 10 15

Ser?Leu?Arg?Leu?Ser?Cys?Ala?Ala?Ser?Gly?Phe?Thr?Phe?Ser?Ser?Tyr

20 25 30

Ala?Met?Ser?Trp?Val?Arg?Gln?Ala?Pro?Gly?Lys?Gly?Leu?Glu?Trp?Val

35 40 45

Ser?Ala?Ile?Ser?Gly?Ser?Gly?Gly?Ser?Thr?Tyr?Tyr?Ala?Asp?Ser?Val

50 55 60

Lys?Gly?Arg?Phe?Thr?Ile?Ser?Arg?Asp?Asn?Ser?Lys?Asn?Thr?Leu?Tyr

65 70 75 80

Leu?Gln?Met?Asn?Ser?Leu?Arg?Ala?Glu?Asp?Thr?Ala?Val?Tyr?Tyr?Cys

85 90 95

Ala?Lys

<210>83

<211>12

<212>PRT

＜213〉homo sapiens

<220>

<221>MISC_FEATURE

<222>(1)..(2)

<223>CDR3

<220>

<221>MISC_FEATURE

<222>(3)..(12)

<223>FR4

<400>83

Leu?Thr?Phe?Gly?Gly?Gly?Thr?Lys?Val?Glu?Ile?Lys

1 5 10

<210>84

<211>15

<212>PRT

＜213〉homo sapiens

<220>

<221>MISC_FEATURE

<222>(1)..(4)

<223>CDR3

<220>

<221>MISC_FEATURE

<222>(5)..(15)

<223>FR4

<400>84

Tyr?Phe?Asp?Tyr?Trp?Gly?Gln?Gly?Thr?Leu?Val?Thr?Val?Ser?Ser

1 5 10 15

<210>85

<211>68

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source Vk

<400>85

gagctccaga?tgacccagtc?tccatcctcc?ctgtctgcat?ctgtaggtga?ccgcgtcacc 60

atcacttg 68

<210>86

<211>69

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source Vk

<400>86

attcagatat?gggctgccat?aagtgtgcag?gaggctctga?ctggagcggc?aagtgatggt 60

gacgcggtc 69

<210>87

<211>66

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source Vk

<400>87

tatggcagcc?catatctgaa?ttggtatctc?cagaaaccag?gccagtctcc?taagctcctg 60

atctat 66

<210>88

<211>65

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source Vk

<400>88

ctgaaacgtg?atgggacacc?actgaaacga?ttggacactt?tatagatcag?gagcttagga 60

gactg 65

<210>89

<211>90

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source Vk

<400>89

agtggtgtcc?catcacgttt?cagtggcagt?ggttctggca?cagatttcac?tctcaccatc 60

agcagtctgc?aacctgaaga?ttttgcagtg 90

<210>90

<211>87

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source Vk

<400>90

gatctccacc?ttggtccctc?cgccgaaagt?ataagggagg?tgggtgccct?gactacagaa 60

gtacactgca?aaatcttcag?gttgcag 87

<210>91

<211>79

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source VH

<400>91

gaggtgcagc?tggtggagtc?tggcggtggc?ttggtacagc?ctggcggttc?cctgcgcctc 60

tcctgtgcag?cctctggct 79

<210>92

<211>81

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source VH

<400>92

ctccaggccc?ttctctggag?actggcggac?ccagctcatc?caatagttgc?taaaggtgaa 60

gccagaggct?gcacaggaga?g 81

<210>93

<211>81

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source VH

<400>93

tctccagaga?agggcctgga?gtgggtctca?gagattcgtc?tgcgcagtga?caactacgcc 60

acgcactatg?cagagtctgt?c 81

<210>94

<211>73

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source VH

<400>94

cagatacagc?gtgttcttgg?aattgtcacg?ggagatggtg?aagcggccct?tgacagactc 60

tgcatagtgc?gtg 73

<210>95

<211>76

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source VH

<400>95

caattccaag?aacacgctgt?atctgcaaat?gaacagcctg?cgcgccgagg?acacgggcat 60

ttattactgt?aaaacg 76

<210>96

<211>79

<212>DNA

＜213〉artificial sequence

<220>

＜223〉the PCR primer of generation people source VH

<400>96

tgaggagacg?gtgaccaggg?tgccctggcc?ccagtagctg?aaactgtaga?agtacgtttt 60

acagtaataa?atgcccgtg 79

<210>97

<211>48

<212>DNA

＜213〉artificial sequence

<220>

＜223〉be used to the to increase PCR primer of h38C2 VH encoding sequence

<400>97

gaggaggagg?aggaggagct?cactccgagg?tgcagctggt?ggagtctg 48

<210>98

<211>72

<212>DNA

＜213〉artificial sequence

<220>

<223>PCR?primer?for?amplifying?h38C2?VL?coding?sequence

<400>98

gaggaggagg?aggagaagct?tgttgctctg?gatctctggt?gcctacgggg?agctccagat 60

gacccagtct?cc 72

<210>99

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 38 go up Pro by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(38)..(38)

＜223〉Methionin (SH)

<400>99

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Xaa?Ser

35

<210>100

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 36 go up Pro by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(36)..(36)

＜223〉Methionin (SH)

<400>100

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Xaa?Pro?Pro?Ser

35

<210>101

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 34 go up Gly by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(34)..(34)

＜223〉Methionin (SH)

<400>101

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Xaa?Ala?Pro?Pro?Pro?Ser

35

<210>102

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 28 go up Asn by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(28)..(28)

＜223〉Methionin (SH)

<400>102

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Xaa?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>103

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 26 go up Leu by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(26)..(26)

＜223〉Methionin (SH)

<400>103

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Xaa?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>104

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 24 go up Glu by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(24)..(24)

＜223〉Methionin (SH)

<400>104

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Xaa?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>105

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 23 go up Ile by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(23)..(23)

＜223〉Methionin (SH)

<400>105

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Xaa?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>106

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 21 go up Leu by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(21)..(21)

＜223〉Methionin (SH)

<400>106

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Xaa?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>107

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 20 go up Arg by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin (SH)

<400>107

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Xaa?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>108

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 19 go up Val by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(19)..(19)

＜223〉Methionin (SH)

<400>108

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Xaa?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>109

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 17 go up Glu by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(17)..(17)

＜223〉Methionin (SH)

<400>109

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Xaa?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>110

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 16 go up Glu by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉Methionin (SH)

<400>110

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Xaa

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>111

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 14 go up Met by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(14)..(14)

＜223〉Methionin (SH)

<400>111

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Xaa?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?PheIle?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>112

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 13 go up Gln by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(13)..(13)

＜223〉Methionin (SH)

<400>112

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Xaa?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>113

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 11 go up Ser by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(11)..(11)

＜223〉Methionin (SH)

<400>113

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Xaa?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?PheIle?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>114

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Gly by Aib2 substitute, 31 go up that Pro is substituted by Lys (SH) and the Exendin-4 peptide of 8 amino acid carboxyls brachymemma

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(31)

＜223〉Methionin (SH)

<400>114

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Xaa

20 25 30

<210>115

<211>33

<212>PRT

＜213〉artificial sequence

<220>

＜223〉upward Gly is alternative by Aib2,21 upward leu is alternative by Lys, 27 upward Lys is alternative by Lys (SH) to have 2

Exendin-4 peptide with the brachymemma of 6 amino acid carboxyls

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(27)..(27)

＜223〉Methionin (SH)

<400>115

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Lys?PheIle?Glu?Trp?Leu?Xaa?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser

<210>116

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 10 go up Val by Lys (SH) substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(10)..(10)

＜223〉Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>116

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Xaa?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>117

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 12 go up Ser by Lys (SH) substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(12)..(12)

＜223〉Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>117

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Xaa?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>118

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 14 go up Leu by Lys (SH) substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(14)..(14)

＜223〉Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>118

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Xaa?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>119

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Lys (SH) substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>119

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>120

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 18 go up Ala by Lys (SH) substitute, 19 go up Ala by Val substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(18)..(18)

＜223〉Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>120

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Xaa?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>121

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 20 go up Lys by Lys (SH) substitute, 22 go up Phe by Lys substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>121

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Xaa?Glu?Lys?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>122

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 24 go up Ala by Lys (SH) substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(24)..(24)

＜223〉Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>122

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Xaa?Trp?Leu?Ile?Lys?Xaa?Arg

20 25 30

<210>123

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 26 go up Leu by Lys (SH) substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(26)..(26)

＜223〉Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>123

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Xaa?Ile?Lys?Xaa?Arg

20 25 30

<210>124

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉GLP-1 (7-36)/exendin-4 fusogenic peptide

<220>

<221>MISC_FEATURE

<222>(1)..(30)

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(39)

＜223〉corresponding to the 31-39 residue of exendin-4

<220>

<221>MISC_FEATURE

<222>(40)..(40)

＜223〉Methionin (SH)

<400>124

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Xaa

35 40

<210>125

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 28 and go up Lys by Arg alternate GLP-1 (7-36) peptide

<400>125

His?Ala?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Gly?Arg

20 25 30

<210>126

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 20 go up Lys by Arg substitute, 28 go up that Lys is substituted by Arg and the C-end adds GLP-1 (7-36) peptide of Lys

<400>126

His?Ala?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Gly?Arg?Lys

20 25 30

<210>127

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 20 go up Lys by Arg substitute, 28 go up that Lys is substituted by Arg and 30 go up Arg by Lys alternate GLP-1 (7-36) peptide

<400>127

His?Ala?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Gly?Lys

20 25 30

<210>128

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up that Gly is substituted by Aib2 and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>128

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>129

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Ala are substituted by Aib2 and 16 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<400>129

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg

20 25 30

<210>130

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Aib2 substitute, 20 go up Lys by Arg substitute, 28 go up Lys by Arg substitute, 29 go up that Gly is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>130

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Xaa?Arg?Lys

20 25 30

<210>131

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 20 go up Lys by Arg substitute, 28 go up Lys by Arg substitute, 29 go up that Gly is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>131

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Xaa?Arg?Lys

20 25 30

<210>132

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Aib2 substitute, 20 go up Lys by Arg substitute, 28 go up that Lys is substituted by Arg and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<400>132

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Gly?Arg?Lys

20 25 30

<210>133

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Aib2 substitute, 20 go up that Lys is substituted by Arg and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>133

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg

20 25 30

<210>134

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 20 go up that Lys is substituted by Arg and and the C-end add GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>134

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Lys

20 25 30

<210>135

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Aib2 substitute, 20 go up that Lys is substituted by Arg and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<400>135

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Arg?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Lys

20 25 30

<210>136

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Aib2 substitute, 28 go up that Lys is substituted by Arg and 29 go up Gly by Aib2 alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>136

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Xaa?Arg

20 25 30

<210>137

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 28 go up Lys by Arg substitute, 29 go up that Gly is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>137

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Xaa?Arg?Lys

20 25 30

<210>138

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Aib2 substitute, 28 go up that Lys is substituted by Arg and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<400>138

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Arg?Gly?Arg?Lys

20 25 30

<210>139

<211>32

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Aib2 substitute, 29 go up that Gly is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>139

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg?Ala?Lys

20 25 30

<210>140

<211>32

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 29 go up that Gly is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Ala-Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>140

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg?Ala?Lys

20 25 30

<210>141

<211>32

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up that Gly is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Ala-Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<400>141

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Ala?Lys

20 25 30

<210>142

<211>31

<212>PRT

＜213〉artificial sequence

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<400>142

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Xaa?Arg?Lys

20 25 30

<210>143

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up that Gly is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<400>143

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Lys

20 25 30

<210>144

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up that Ala is substituted by D-Ala and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

<223>D-Alanine

<400>144

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Lys

20 25 30

<210>145

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Aib2 substitute, 19 go up that Ala is substituted by Aib2 and the C-end adds GLP-1 (7-36) peptide of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(19)..(19)

＜223〉2-aminoisobutyric acid

<400>145

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Xaa

1 5 10 15

Gln?Ala?Xaa?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg?Lys

20 25 30

<210>146

<211>31

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have respectively at 2,16,17,20,24 and 28 go up Ala by Aib2 substitute, Gly by Glu substitute, Gln by Glu substitute, Lys by Arg, Ala by Glu and Lys by Arg alternate GLP-1 (7-36) peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<400>146

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Glu?Ala?Ala?Arg?Glu?Phe?Ile?Glu?Trp?Leu?Val?Arg?Gly?Arg?Lys

20 25 30

<210>147

<211>45

<212>PRT

＜213〉artificial sequence

<220>

＜223〉has the Exendin-4 peptide that the C-end adds six Lys

<400>147

His?Gly?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Lys?Lys Lys?Lys Lys Lys

35 40 45

<210>148

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 last Gly and substitute the Exendin-4 peptide that links to each other with joint L with 27 last Lys by Aib2

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(27)..(27)

＜223〉Methionin that links to each other with joint L

<400>148

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Xaa?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>149

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 21 go up Leu by Lys alternate Exendin-4 peptide, wherein the Lys on 21 links to each other with joint L

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(21)..(21)

＜223〉Methionin that links to each other with joint L

<400>149

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Xaa?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>150

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 20 go up Arg by Lys alternate Exendin-4 peptide, wherein the Lys on 20 links to each other with joint L

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin that links to each other with joint L

<400>150

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Xaa?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>151

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 19 go up Val by Lys alternate Exendin-4 peptide, wherein the Lys on 19 links to each other with joint L

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(19)..(19)

＜223〉Methionin that links to each other with joint L

<400>151

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Xaa?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>152

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 14 go up Met by Lys alternate Exendin-4 peptide, wherein the Lys on 14 links to each other with joint L

<220>

<221>MISC_FEAIURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(14)..(14)

＜223〉Methionin that links to each other with joint L

<400>152

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Xaa?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>153

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉GLP-1 (7-36)/exendin-4 fusogenic peptide

<220>

<221>MISC_FEATURE

<222>(1)..(30)

＜223〉have 2 go up Gly by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Val by Lys substitute, 27 go up that Val is substituted by Ile and 29 go up Gly by Aib2 alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(39)

＜223〉corresponding to the 31-39 residue of exendin-4

<220>

<221>MISC_FEATURE

<222>(40)..(40)

＜223〉Methionin that links to each other with joint L

<400>153

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Xaa

35 40

<210>154

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉GLP-1 (7-36)/exendin-4 fusogenic peptide

<220>

<221>MISC_FEATURE

<222>(1)..(30)

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val alternate, 27 go up Val by Ile substitute, 29 go up Gly by Aib2 substitute with 20 on the GLP-1 peptide that links to each other with joint L of Lys

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin that links to each other with joint L

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(39)

＜223〉corresponding to the 31-39 residue of exendin-4

<400>154

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Xaa?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>155

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 last Ala and substitute GLP-1 (7-36) peptide that links to each other with joint L with 20 last Lys by Aib2

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin that links to each other with joint L

<400>155

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Xaa?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg

20 25 30

<210>156

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 last Gly and substitute the Exendin-4 peptide that links to each other with joint L ' with 27 last Lys by Aib2

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(27)..(27)

＜223〉Methionin that links to each other with joint L '

<400>156

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Xaa?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>157

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 last Gly and substitute the Exendin-4 peptide that links to each other with joint L ' with 21 last Lys by Aib2

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(21)..(21)

＜223〉Methionin that links to each other with joint L '

<400>157

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Xaa?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>158

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 last Gly and substitute the Exendin-4 peptide that links to each other with joint L ' with 20 last Lys by Aib2

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin that links to each other with joint L '

<400>158

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Xaa?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>159

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 last Gly and substitute the Exendin-4 peptide that links to each other with joint L ' with 19 last Lys by Aib2

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(19)..(19)

＜223〉Methionin that links to each other with joint L '

<400>159

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Xaa?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>160

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 last Gly and substitute the Exendin-4 peptide that links to each other with joint L ' with 14 last Lys by Aib2

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(14)..(14)

＜223〉Methionin that links to each other with joint L '

<400>160

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Xaa?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>161

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉GLP-1 (7-36)/exendin-4 fusogenic peptide

<220>

<221>MISC_FEATURE

<222>(1)..(30)

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(39)

＜223〉corresponding to the 31-39 residue of exendin-4

<220>

<221>MISC_FEATURE

<222>(40)..(40)

＜223〉Methionin that links to each other with joint L

<400>161

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Lys?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Xaa

35 40

<210>162

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉GLP-1 (7-36)/exendin-4 fusogenic peptide

<220>

<221>MISC_FEATURE

<222>(1)..(30)

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val substitute, 27 go up Val by Ile substitute, 29 go up Gly and substitute with 20 by Aib2 and go up the GLP-1 peptide that Lys links to each other with L '

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin that links to each other with joint L '

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(39)

＜223〉corresponding to the 31-39 residue of exendin-4

<400>162

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Xaa?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>163

<211>30

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 last Gly and substitute GLP-1 (7-36) peptide that links to each other with joint L ' with 20 last Lys by Aib2

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin that links to each other with joint L '

<400>163

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Gly

1 5 10 15

Gln?Ala?Ala?Xaa?Glu?Phe?Ile?Ala?Trp?Leu?Val?Lys?Gly?Arg

20 25 30

<210>164

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 16 go up Glu by Lys alternate Exendin-4 peptide, wherein the Lys on 16 links to each other with joint L

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉Methionin that links to each other with joint L

<400>164

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Xaa

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>165

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 16 go up Glu by Lys alternate Exendin-4 peptide, wherein the Lys on 16 links to each other with joint L '

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(16)..(16)

＜223〉Methionin that links to each other with joint L '

<400>165

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Xaa

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>166

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have the Exendin-4 peptide that C-end adds Lys, wherein the Lys on 40 links to each other with joint L

<220>

<221>MISC_FEATURE

<222>(40)..(40)

＜223〉Methionin that links to each other with joint L

<400>166

His?Gly?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Xaa

35 40

<210>167

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up that Gly is substituted by Aib2 and the C-end adds the Exendin-4 peptide of Lys, wherein the Lys on 40 links to each other with joint L

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(40)..(40)

＜223〉Methionin that links to each other with joint L

<400>167

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Xaa

35 40

<210>168

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 32 go up Ser by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(32)..(32)

＜223〉Methionin (SH)

<400>168

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Xaa

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>169

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 12 go up Lys by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(12)..(12)

＜223〉Methionin (SH)

<400>169

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Xaa?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>170

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 go up that Gly are substituted by Aib2 and 27 go up Lys by K (SH) alternate Exendin-4 peptide

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(27)..(27)

＜223〉Methionin (SH)

<400>170

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Xaa?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>171

<211>39

<212>PRT

＜213〉artificial sequence

<220>

＜223〉GLP-1 (7-36)/exendin-4 fusogenic peptide

<220>

<221>MISC_FEATURE

<222>(1)..(30)

＜223〉have 2 go up Ala by Aib2 substitute, 16 go up Gly by Glu substitute, 19 go up Ala by Val alternate, 27 go up Val by Ile substitute, 29 go up that Gly is substituted by Aib2 and 20 on the GLP-1 peptide of Lys (SH)

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(20)..(20)

＜223〉Methionin (SH)

<220>

<221>MISC_FEATURE

<222>(29)..(29)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(31)..(39)

＜223〉corresponding to the 31-39 residue of exendin-4

<400>171

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Val?Ser?Ser?Tyr?Leu?Glu?Glu

1 5 10 15

Gln?Ala?Val?Xaa?Glu?Phe?Ile?Ala?Trp?Leu?Ile?Lys?Xaa?Arg?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser

35

<210>172

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉has the Exendin-4 peptide that the C-end adds Lys (SH)

<220>

<221>MISC_FEATURE

<222>(40)..(40)

<223>Lys(SH)

<400>172

His?Gly?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?Gly?Ala?Pro?Pro?Pro?Ser?Xaa

35 40

<210>173

<211>40

<212>PRT

＜213〉artificial sequence

<220>

＜223〉have 2 and go up that Gly is substituted by Aib2 and the C-end adds the Exendin-4 peptide of Lys (SH)

<220>

<221>MISC_FEATURE

<222>(2)..(2)

＜223〉2-aminoisobutyric acid

<220>

<221>MISC_FEATURE

<222>(40)..(40)

＜223〉Methionin (SH)

<400>173

His?Xaa?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?Glu?Glu

1 5 10 15

Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?Ser

20 25 30

Ser?G1y?Ala?Pro?Pro?Pro?Ser?Xaa

35 40

Claims

1. GA target agent, wherein this GA target agent is the peptide agonists of GLP-1 acceptor, the agent of described GA target comprises the peptide that comprises with the basic homologous sequence of following sequence:

R ¹-H ¹x ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹x ¹⁰S ¹¹x ¹²x ¹³x ¹⁴E ¹⁵x ¹⁶x ¹⁷A ¹⁸x ¹⁹x ²⁰x ²¹F ²²x ²³x ²⁴x ²⁵x ²⁶x ²⁷x ²⁸x ²⁹x ³⁰x ³¹x ³²x ³³x ³⁴x ³⁵x ³⁶x ³⁷x ³⁸x ³⁹-R ², wherein:

R ¹Disappearance, or CH ₃, C (O) CH3, C (O) CH ₂CH ₃, C (O) CH ₂CH ₂CH ₃Or C (O) CH (CH ₃) CH ₃

R ²Disappearance, or OH, NH ₂, NH (CH ₃), NHCH ₂CH ₃, NHCH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₃, NHCH ₂CH ₂CH ₂CH ₃, NHCH (CH ₃) CH ₂CH ₃, NHC ₆H ₅, NHCH ₂CH ₂OCH ₃, NHOCH ₃, NHOCH ₂CH ₃, carboxyl-protecting group, lipid is fatty acid-based or sugared;

x ²Be such as blocking groups such as Aib, A, S, T, V, L, I, D-Ala;

x ¹⁰Be V, L, I or A;

x ¹²Be S or K;

x ¹³Be Q or Y;

x ¹⁴Be G, C, F, Y, W, M or L;

x ¹⁶Be K, D, E or G;

x ¹⁷Be E or Q;

x ¹⁹Be L, I, V or A;

x ²⁰Be Orn, K (SH), R or K;

x ²¹Be L or E;

x ²³Be I or L;

x ²⁴Be A or E;

x ²⁵Be W or F;

x ²⁶Be L or I;

x ²⁷Be I, K or V;

x ²⁸Be R, Orn, N or K;

x ²⁹Be Aib or G;

x ³⁰Be any amino acid, be preferably G or R;

x ³¹Be P or disappearance;

x ³²Be S or disappearance;

x ³³Be S or disappearance;

x ³⁴Be G or disappearance;

x ³⁵Be A or disappearance;

x ³⁶Be P or disappearance;

x ³⁷Be P or disappearance;

x ³⁸Be P or disappearance;

x ³⁹Be S or disappearance; With

x ⁴⁰Be to connect residue or disappearance;

X wherein ¹⁰, x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁷, x ¹⁹, x ²⁰, x ²¹, x ²⁴, x ²⁶, x ²⁷, x ²⁸, x ³², x ³³, x ³⁴, x ³⁵, x ³⁶, x ³⁷, x ³⁸, x ³⁹Or x ⁴⁰One of by connecting residue-[LR]-replacements, described connection residue comprises can be with antibody combining site direct or through the covalently bound nucleophilic side chain of intermediate head, and wherein said connection residue is K (SH).

2. GA target as claimed in claim 1 agent, wherein x ²Be Aib.

3. each described GA target agent in the claim as described above, it comprises the peptide that comprises with the basic homologous sequence of following sequence:

R ¹-H ¹Aib ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹V ¹⁰S ¹¹S ¹²Y ¹³x ¹⁴E ¹⁵x ¹⁶Q ¹⁷A ¹⁸x ¹⁹x ²⁰E ²¹F ²²I ²³A ²⁴x ²⁵L ²⁶x ²⁷x ²⁸x ²⁹R ³⁰-R ², wherein:

x ¹⁴Be G, C, F, Y, W or L;

x ¹⁶Be K, D, E or G;

x ¹⁹Be L, I, V or A;

x ²⁰Be Orn, R or K;

x ²⁵Be W or F;

x ²⁷Be I or V;

x ²⁸Be R or K; With

x ²⁹Be Aib or G.

4. each described GA target agent in the claim as described above, it comprises the peptide that comprises with the basic homologous sequence of following sequence:

5. each described GA target agent in the claim as described above, wherein said connection residue is selected from x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁷, x ¹⁹, x ²⁰, x ²¹, x ²⁴, x ²⁷, x ²⁸, x ³², x ³⁴, x ³⁸Hold with C.

6. each described GA target agent in the claim as described above, wherein said connection residue is selected from x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁹, x ²⁰, x ²¹, x ²⁷, x ²⁸, x ³²And x ³⁴

7. each described GA target agent in the claim as described above, wherein said connection residue is selected from x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁹, x ²⁰And x ²¹

8. each described GA target agent in the claim as described above, wherein said connection residue is selected from x ¹³, x ¹⁴, x ¹⁶, x ¹⁹, x ²⁰And x ²¹

9. each described GA target agent in the claim as described above, wherein said connection residue is x ¹⁴

10. each agent of described GA target, wherein R in the claim as described above ¹Be C (O) CH ₃

11. each agent of described GA target, wherein R in the claim as described above ²Be NH ₂

12. GA target as claimed in claim 1 agent, the agent of wherein said GA target comprise the peptide that comprises and be selected from the basic homologous sequence of one or more compounds of following compounds:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)，

R ¹-HAIBEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAIBEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAIBEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGK(SH)-R ²(SEQ?ID?NO：114)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)，

R ¹-HAIBEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)，

R ¹-HAIBEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)，

R ¹-HAIBEGTFTSDVSSYLEEQAVK(SH)EFIAWLIKAIBRPSSGAPPPS-R ²(SEQ?ID?NO：171)，

R ¹-HAIBEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAIBR-R ²(SEQ?ID?NO：116)，

R ¹-HAIBEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAIBR-R ²(SEQ?ID?NO：117)，

R ¹-HAIBEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAIBR-R ²(SEQ?ID?NO：118)，

R ¹-HAIBEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAIBR-R ²(SEQ?ID?NO：119)，

R ¹-HAIBEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAIBR-R ²(SEQ?ID?NO：120)，

R ¹-HAIBEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAIBR-R ²(SEQ?ID?NO：121)，

R ¹-HAIBEGTFTSDVSSYLEEQAVKEFIK(SH)WLIKAIBR-R ²(SEQ?ID?NO：122)，

R ¹-HAIBEGTFTSDVSSYLEEQAVKEFIAWK (SH) IKAIBR-R ²(SEQ ID NO:123) and

R ¹-HAIBEGTFTSDVSSYLEEQAVKEFIAWLIKAIBRPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：124)。

13. GA target as claimed in claim 1 agent, the agent of wherein said GA target comprise the peptide that comprises and be selected from the basic homologous sequence of one or more compounds of following compounds:

R ¹-HAIBEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)，

R ¹-HAIBEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)，

R ¹-HAIBEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAIBR-R ²(SEQ?ID?NO：116)，

R ¹-HAIBEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAIBR-R ²(SEQ?ID?NO：117)，

R ¹-HAIBEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAIBR-R ²(SEQ?ID?NO：118)，

R ¹-HAIBEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAIBR-R ²(SEQ?ID?NO：119)，

R ¹-HAIBEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAIBR-R ²(SEQ?ID?NO：120)，

R ¹-HAIBEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAIBR-R ²(SEQ?ID?NO：121)，

R ¹-HAIBEGTFTSDVSSYLEEQAVKEFIK (SH) WLIKAIBR-R ²(SEQ ID NO:122) and

R ¹-HAIBEGTFTSDVSSYLEEQAVKEFIAWK(SH)IKAIBR-R ²(SEQ?ID?NO：123)。

14. GA target as claimed in claim 1 agent, the agent of wherein said GA target comprise the peptide that comprises and be selected from the basic homologous sequence of one or more compounds of following compounds:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)，

R ¹-HAIBEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAIBEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAIBEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGK (SH)-R ²(SEQ ID NO:114) and

R ¹-HAIBEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)。

15. GA target as claimed in claim 14 agent, the agent of wherein said GA target comprise the peptide that comprises and be selected from the basic homologous sequence of one or more compounds of following compounds:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)，

R ¹-HAIBEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAIBEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAIBEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGK (SH)-R ²(SEQ ID NO:114) and

R ¹-HAIBEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)。

16. comprising, GA target as claimed in claim 1 agent, the agent of wherein said GA target comprise the peptide that is selected from following sequence:

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAIBEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAIBEGTFTSDLK (SH) KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ ID NO:113) and

R ¹-HAIBEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)。

17. comprising, GA target as claimed in claim 1 agent, the agent of wherein said GA target comprise the peptide that is selected from following sequence:

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEK (SH) EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ ID NO:110) and

R ¹-HAIBEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)。

18. compound that structure is following:

19. compound with following formula:

The agent of L-[GA target] or L '-[agent of GA target]

Wherein:

[agent of GA target] is each described GA target agent in the claim as described above;

L is the joint with formula-X-Y-Z-;

L ' is the shank with formula-X-Y-Z ';

L or L ' are with described to be connected residue covalently bound;

X randomly exists and is the biocompatibility connection chain that comprises any atom that is selected from C, H, N, O, P, S, F, Cl, Br and I, and can comprise polymkeric substance or segmented copolymer;

Y is the recognition group that comprises at least one ring structure that randomly exists;

Z is the reactive group that can form covalent linkage with the amino acid side chain in the antibody combining site; Know

Z ' comprises the covalently bound attachment portion that links to each other with amino acid side chain in the antibody combining site.

20. compound as claimed in claim 19, wherein

X links to each other with the residue that is connected of described GA target agent, and it is substituted or is not substituted, and is selected from-R ²²-[CH ₂-CH ₂-O] _t-R ²³-,-R ²²-cycloalkyl-R ²³-,-R ²²-aryl-R ²³-and R ²²-heterocyclic radical-R ²³-, wherein:

R ²²And R ²³Be selected from independently of one another covalent linkage ,-O-,-S-,-NR ^b-, replacement or unsubstituted straight or branched C _1-50Alkylidene group, replacement or unsubstituted straight or branched C _1-50Assorted alkylidene group, replacement or unsubstituted straight or branched C _2-50Alkenylene or replacement or unsubstituted C _2-50Assorted alkenylene;

R ^bWhen occurring, be independently selected from hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement and unsubstituted aryl-C _0-6Alkyl;

T=2～50; With

R ²²And R ²³Size make the backbone length of X be maintained at about 200 atoms or about 200 below the atom.

21. compound as claimed in claim 20, wherein:

R ²²Be selected from-(CH ₂) _v-,-(CH ₂) _u-C (O)-(CH ₂) _v-,-(CH ₂) _u-C (O)-O-(CH ₂) _v-,-(CH ₂) _u-C (O)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-C (S)-NR ^b-(CH ₂) _v-,-(CH ₂) _u-NR ^b-(CH ₂) _v-,-(CH ₂) _u-O-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-(CH ₂) _v-,-(CH ₂) _u-S (O) _0-2-NR ^b-(CH ₂) _v-and-(CH ₂) _u-P (O) (OR ^b)-O-(CH ₂) _v-, wherein u and v are 0～20 independently;

R ²³Be selected from-O-,-S-,-NR ^b-, replacement or unsubstituted straight or branched C _1-50Alkylidene group, replacement or unsubstituted straight or branched C _1-50Assorted alkylidene group, replacement or unsubstituted straight or branched C _2-50Alkenylene and replacement or unsubstituted C _2-50Assorted alkenylene, and can have structure:

Wherein p is 2～45; W is 1～20; R is 1～20; S is 0～20; And R ^bWhen occurring, be independently selected from hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl or replacement and unsubstituted aryl-C _0-6Alkyl; With

22. compound as claimed in claim 21, wherein the structure of X is selected from:

Wherein the backbone length of X is 1～100 atom.

23. compound as claimed in claim 22, wherein the backbone length of X is 1～50 atom.

24. compound as claimed in claim 23, wherein the backbone length of X is 1～25 atom.

25. compound as claimed in claim 24, wherein the backbone length of X is 1～15 atom.

26. as each described compound in the claim 19～21, wherein X is:

Thereby wherein select v and w to make that the backbone length of X is 6～12 atoms.

27. compound as claimed in claim 26, wherein X-Y is:

Wherein

V is 1 or 2; W is 1 or 2; And R ^bBe hydrogen.

28. GA target as claimed in claim 19 agent, wherein the structure that is connected residue that links to each other with described joint is:

29. as each described compound in the claim 19～28, wherein ring structure Y exists and has a structure of following optional replacement:

Wherein

A, b, c, d and e are carbon or nitrogen independently of one another; F is carbon, nitrogen, oxygen or sulphur; Y links to each other at any two ring position places of enough valence states with Z or Z ' with X independently; And be no more than four among a, b, c, d, e and the f, and a, b, c, d and e in the preferred ring structure carbon of respectively doing for oneself simultaneously for nitrogen.

30. as each described compound in the claim 19～29, wherein said ring structure Y is a phenyl.

31. as each described compound in the claim 19～30, wherein:

If be selected from substituted alkyl, substituted cycloalkyl, substituted aryl, substituted aryl alkyl, substituted heterocyclic radical or substituted heterocyclic radical alkyl when Z exists, wherein at least one substituting group is 1,3-diketone part, acyl group-beta-lactam, active ester, α-Lu Daitong, aldehyde, maleimide, lactone, acid anhydrides, α-Lu Daiyixianan, amine, hydrazine or epoxide; With

Z ' is if be selected from substituted alkyl when existing; substituted cycloalkyl; substituted aryl; substituted aryl alkyl; substituted heterocyclic radical or substituted heterocyclic radical alkyl; wherein at least one substituting group is 1; 3-diketone part; acyl group-beta-lactam; active ester; α-Lu Daitong; aldehyde; maleimide; lactone; acid anhydrides; α-Lu Daiyixianan; amine; hydrazine or epoxide; perhaps by the amino and 1 on the amino acid side chain in the antibody combining site, 3-diketone part; acyl group-beta-lactam; active ester; α-Lu Daitong; aldehyde; maleimide; lactone; acid anhydrides; α-Lu Daiyixianan; amine; the formed product of the addition of hydrazine or epoxide.

32. compound as claimed in claim 31; wherein at least one substituting group is selected from and replaces 1; 3-diketone or acyl group-beta-lactam, and by the amino and 1 on the amino acid side chain in the antibody combining site, the formed product of addition of 3-diketone part or acyl group-beta-lactam.

33. as claim 31 and 32 each described compounds, wherein:

Replace 1 if be selected from when Z exists, 3-diketone, acyl group-beta-lactam, alkyl replace 1, acyl group-beta-lactam that 3-diketone and alkyl replace; With

Z ' is if be by the amino on the amino acid side chain in the antibody combining site and the formed product of part addition when existing; described part is selected from and replaces 1; 3-diketone, acyl group-beta-lactam, alkyl replace 1, acyl group-beta-lactam that 3-diketone and alkyl replace.

34. as each described compound in the claim 19～33, if having structure when wherein Z exists:

And wherein Z ' is if having structure when existing:

If when wherein q=0～5 and antibody exist be the covalent linkage that links to each other with the antibody combining site side chain.

35. as each described GA target compound in the claim 19～34, wherein structure L is when with described the connection when residue links to each other being

U is 1,2 or 3; V is 1 or 2, and t is 1,2 or 3, and r is 1 or 2; S be 0 and q be 1 or 2.

36. GA target compound as claimed in claim 35, wherein u is 2, and v is 2, and t is 2, r be 2 and q be 2.

37. the compound of a following formula:

38. the compound of a following formula:

39. the compound of a following formula:

40. the compound of a following formula:

41. the compound of a following formula:

42. the compound of a following formula:

43. the compound of a following formula:

44. the compound of a following formula:

45. the compound of a following formula:

46. the compound of a following formula:

47. as each described compound in the claim 19～46, wherein Z group and antibody combining site are covalently bound.

48. GA target agent, the agent of wherein said GA target is the peptide agonists of GLP-1 acceptor, and the agent of described GA target comprises the peptide that comprises with the basic homologous sequence of following sequence:

Wherein

x ²Be such as blocking groups such as Aib, A, S, T, V, L, I, D-Ala;

x ¹⁰Be V, L, I, or A;

x ¹²Be S or K;

x ¹³Be Q or Y;

x ¹⁴Be G, C, F, Y, W, M, or L;

x ¹⁶Be K, D, E, or G;

x ¹⁷Be E or Q;

x ¹⁹Be L, I, V, or A;

x ²⁰Be Orn, K (SH), R, or K;

x ²¹Be L or E;

x ²³Be I or L;

x ²⁴Be A or E;

x ²⁵Be W or F;

x ²⁶Be L or I;

x ²⁷Be I, K, or V;

x ²⁸Be R, Orn, N, or K;

x ²⁹Be Aib or G;

x ³⁰Be any amino acid, be preferably G or R;

x ³¹Be P or disappearance;

x ³²Be S or disappearance;

x ³³Be S or disappearance;

x ³⁴Be G or disappearance;

x ³⁵Be A or disappearance;

x ³⁶Be P or disappearance;

x ³⁷Be P or disappearance;

x ³⁸Be P or disappearance;

x ³⁹Be S or disappearance; With

x ⁴⁰Be to connect residue or disappearance;

Wherein said peptide is covalently bound through intermediate head L ' and antibody combining site, and L ' hold with C or be connected residue-[LR]-the nucleophilic side chain covalently bound,

Thereby make-[LR]-be selected from K, R, Y, C, T, S, comprise Methionin homologue, homocysteine and the homoserine of K (SH), and when it exists, will replace x ¹⁰, x ¹¹, x ¹², x ¹³, x ¹⁴, x ¹⁶, x ¹⁷, x ¹⁹, x ²⁰, x ²¹, x ²⁴, x ²⁶, x ²⁷, x ²⁸, x ³², x ³³, x ³⁴, x ³⁵, x ³⁶, x ³⁷, x ³⁸, x ³⁹Or x ⁴⁰One of.

49. GA target as claimed in claim 48 agent, wherein x ²Be Aib.

50. as each described GA target agent in the claim 48～49, the agent of wherein said GA target comprises the peptide that comprises with the basic homologous sequence of following sequence:

R ¹-H ¹Aib ²E ³G ⁴T ⁵F ⁶T ⁷S ⁸D ⁹V ¹⁰S ¹¹S ¹²Y ¹³x ¹⁴E ¹⁵x ¹⁶Q ¹⁷A ¹⁸x ¹⁹x ²⁰E ²¹F ²²I ²³A ²⁴x ²⁵L ²⁶x ²⁷x ²⁸x ²⁹R ³⁰-R ²，

X wherein ¹⁴Be G, C, F, Y, W or L;

x ¹⁶Be K, D, E or G;

x ¹⁹Be L, I, V or A;

x ²⁰Be Orn, R or K;

x ²⁵Be W or F;

x ²⁷Be I or V;

x ²⁸Be R or K; With

x ²⁹Be Aib or G.

51. as each described GA target agent in the claim 48～50, the agent of wherein said GA target comprises the peptide that comprises with the basic homologous sequence of following sequence:

52. as each described GA target agent in the claim 48～51, wherein said connection residue is selected from K, Y, T and comprises the Methionin homologue of K (SH).

53. GA target as claimed in claim 52 agent, wherein said connection residue is K.

54. GA target as claimed in claim 52 agent, wherein said connection residue are K (SH).

55. GA target as claimed in claim 52 agent, wherein said connection residue are K (L '), wherein K (L ') is the lysine residue that links to each other with joint L, and described joint L forms covalent linkage with the amino acid side chain of antibody combining site.

56. GA target as claimed in claim 55 agent, wherein K (L ') is

Wherein u is 1,2 or 3; With

-L '-be joint with formula-X-Y-Z ', wherein:

X is:

Wherein v is 0,1,2 or 3; T is 1,2 or 3, and r is 1 or 2; S is 0,1 or 2;

Z ' be comprise with antibody combining site in the covalency of amino acid side chain link the connection portion.

57. compound with following formula:

L '-[agent of GA target]

Wherein:

[agent of GA target] is as each described GA target agent in the claim 48～56; With

L ' is the shank with formula-X-Y-Z ', thereby L ' is with described to be connected residue covalently bound;

Wherein:

58. compound as claimed in claim 57, wherein

X links to each other with the residue that is connected of described GA target agent, and it is substituted or is not substituted, and is selected from-R ²²-[CH ₂-CH ₂-O] _t-R ²³-,-R ²²-cycloalkyl-R ²³-,-R ²²-aryl-R ²³-and-R ²²-heterocyclic radical-R ²³-; Wherein:

R ²²And R ²³Be independently selected from covalent linkage ,-O-,-S-,-NR ^b-, replacement or unsubstituted straight or branched C _1-50Alkylidene group, replacement or unsubstituted straight or branched C _1-50Assorted alkylidene group, replacement or unsubstituted straight or branched C _2-50Alkenylene and replacement or unsubstituted C _2-50Assorted alkenylene;

R ^bWhen occurring, be independently selected from hydrogen, replacement or unsubstituted C _1-10Alkyl, replacement or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl and replacement or unsubstituted aryl-C _0-6Alkyl;

T=2～50; With

59. compound as claimed in claim 58, wherein:

R ²³Be selected from-O-,-S-,-NR ^b-, replacement or unsubstituted straight or branched C _1-50Alkylidene group, replacement or unsubstituted straight or branched C _1-50Assorted alkylidene group, replacement or unsubstituted straight or branched C _2-50Alkenylene and replacement or unsubstituted C _2-50Assorted alkenylene; And can be selected from

Wherein p is 2～45; W is 1～20; R is 1～20; S is 0～20; And R ^bWhen occurring, be independently selected from hydrogen, replacement or unsubstituted C _1-10Alkyl; Replace or unsubstituted C _3-7Cycloalkyl-C _0-6Alkyl and replacement or unsubstituted aryl-C _0-6Alkyl; And

60. compound as claimed in claim 59, wherein the structure of X is selected from:

Wherein the backbone length of X is 1～100 atom.

61. compound as claimed in claim 60, wherein the backbone length of X is 1～50 atom.

62. compound as claimed in claim 61, wherein the backbone length of X is 1～25 atom.

63. compound as claimed in claim 62, wherein the backbone length of X is 1～15 atom.

64. as each described compound among the claim 57-63, wherein X is:

65. as the described compound of claim 64, wherein X-Y is:

Wherein

V=1 or 2; W=1 or 2; R ^bBe hydrogen.

66. as each described compound in the claim 57～65, wherein ring structure Y exists and has a structure of following optional replacement:

Wherein a, b, c, d and e are carbon or nitrogen independently of one another; F is carbon, nitrogen, oxygen or sulphur; Y links to each other at any two ring position places of enough valence states with Z or Z ' with X independently; And be no more than four among a, b, c, d, e and the f, and a, b, c, d and e in the preferred ring structure carbon of respectively doing for oneself simultaneously for nitrogen.

67. as each described compound in the claim 57～66, wherein said ring structure Y is a phenyl.

68. as each described compound in the claim 57～67; wherein Z ' is a substituted alkyl; substituted cycloalkyl; substituted aryl; substituted aryl alkyl; substituted heterocyclic radical or substituted heterocyclic radical alkyl; wherein at least one substituting group is 1; 3-diketone part; acyl group-beta-lactam; active ester; α-Lu Daitong; aldehyde; maleimide; lactone; acid anhydrides; α-Lu Daiyixianan; amine; hydrazine or epoxide; perhaps by the amino and 1 on the amino acid side chain in the antibody combining site, 3-diketone part; acyl group-beta-lactam; active ester; α-Lu Daitong; aldehyde; maleimide; lactone; acid anhydrides; α-Lu Daiyixianan; amine; the formed product of the addition of hydrazine or epoxide.

69. as the described compound of claim 68, wherein Z is by the amino on the amino acid side chain in the antibody combining site and 1,3-diketone part or acyl group-formed product of beta-lactam addition.

70. as claim 68 or 69 each described compounds; wherein Z ' is by the amino on the amino acid side chain in the antibody combining site and the formed product of part addition; described part is selected from and replaces 1; 3-diketone, acyl group-beta-lactam, alkyl replace 1, acyl group-beta-lactam that 3-diketone or alkyl replace.

71. as each described compound in the claim 57～70, wherein Z ' has structure:

And wherein q is 0～5, and if antibody be the covalent linkage that links to each other with the antibody combining site side chain when existing.

72. as each described GA target agent in the claim 48～71, it comprises the peptide that comprises and be selected from the basic homologous sequence of one or more compounds of following compounds:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：2)

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：3)

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：4)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWKKNGGPSSGAPPPS-R ²(SEQ?ID?NO：19)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIKWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：20)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFKEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：21)

R ¹-HAibEGTFTSDLSKQMEEKAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：25)

R ¹-HAibEGTFTSDLKKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：29)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK-R ²(SEQ?ID?NO：30)

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPK-R ²(SEQ?ID?NO：31)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)

R ¹-HAibEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK(SH)SSGAPPPS-R ²(SEQ?ID?NO：114)

R ¹-HAibEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：4)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：5)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGG-R ²(SEQ?ID?NO：6)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKN-R ²(SEQ?ID?NO：7)，

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKN-R ²(SEQ?ID?NO：8)，

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKN-R ²(SEQ?ID?NO：9)，

R ¹-HAibEGTFTSDLSKQLEEEAVRLAIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：10)，

R ¹-HAibEGTFTSDLSKQLEEEAVRLFIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：11)，

R ¹-HAibEGTFTSDLSK(Ac)QMEEEAVRLFIEWLK(Ac)NGGPSSGAPPPS-R ²(SEQ?ID

NO：12)，

R ¹-HAibEGTFTSDLSK (benzoyl) QMEEEAVRLFIEWLK (benzoyl) NGGPSSGAPPPS-R ²

(SEQ?ID?NO：13)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPKS-R ²(SEQ?ID?NO：14)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAKPPS-R ²(SEQ?ID?NO：15)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSKAPPPS-R ²(SEQ?ID?NO：16)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPKSGAPPPS-R ²(SEQ?ID?NO：17)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKKGGPSSGAPPPS-R ²(SEQ?ID?NO：18)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWKKNGGPSSGAPPPS-R ²(SEQ?ID?NO：19)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIKWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：20)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFKEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：21)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)，

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)，

R ¹-HAibEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAibEGTFTSDLSKQMEEEAVKLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)，

R ¹-HAibEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAibEGTFTSDLSKQMEEEAKRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)，

R ¹-HAibEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAibEGTFTSDLSKQMEEKAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：25)，

R ¹-HAibEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)，

R ¹-HAibEGTFTSDLSKQMEKEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)，

R ¹-HAibEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAibEGTFTSDLSKQKEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)，

R ¹-HAibEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAibEGTFTSDLSKKMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：28)，

R ¹-HAibEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAibEGTFTSDLKKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：29)，

R ¹-HAibEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK-R ²(SEQ?ID?NO：30)，

R ¹-HAibEGTFTSDLSKQMEEEAVRLFIEWLKNGGK(SH)-R ²(SEQ?ID?NO：114)，

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLKNGGPSS-R ²(SEQ?ID?NO：31)，

R ¹-HAibEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGR-R ²(SEQ?ID?NO：32)，

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：33)，

R ¹-HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：34)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：35)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibRK-R ²(SEQ?ID?NO：36)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：37)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)，

R ¹-HAibEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)，

R ¹-HAibEGTFTSDVSSYGEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：40)，

R ¹-HAibEGTFTSDVSSYCEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：41)，

R ¹-HAibEGTFTSDVSSYFEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：42)，

R ¹-HAibEGTFTSDVSSYYEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：43)，

R ¹-HAibEGTFTSDVSSYWEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：44)，

R ¹-HAibEGTFTSDVSSYLEEQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：45)，

R ¹-HAibEGTFTSDVSSYLEDQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：46)，

R ¹-HAibEGTFTSDVSSYLEKQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：47)，

R ¹-HAibEGTFTSDVSSYLEGQAVKEFIAWLVKAibR-R ²(SEQ?ID?NO：48)，

R ¹-HAibEGTFTSDVSSYLEGQAIKEFIAWLVKAibR-R ²(SEQ?ID?NO：49)，

R ¹-HAibEGTFTSDVSSYLEGQALKEFIAWLVKAibR-R ²(SEQ?ID?NO：50)，

R ¹-HAibEGTFTSDVSSYLEGQAAREFIAWLVKAibR-R ²(SEQ?ID?NO：51)，

R ¹-HAibEGTFTSDVSSYLEGQAAOrnEFIAWLVKAibR-R ²(SEQ?ID?NO：52)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAFLVKAibR-R ²(SEQ?ID?NO：53)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLIKAibR-R ²(SEQ?ID?NO：54)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVRAibR-R ²(SEQ?ID?NO：55)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVOrnAibR-R ²(SEQ?ID?NO：56)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：57)，

R ¹-HAibEGTFTSDVSSYFEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：58)，

R ¹-HAibEGTFTSDVSSYYEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：59)，

R ¹-HAibEGTFTSDVSSYWEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：60)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIRAibR-R ²(SEQ?ID?NO：61)，

R ¹-HAibEGTFTSDVSSYLEEQAVREFIAWLIRAibR-R ²(SEQ?ID?NO：62)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：63)，

R ¹-HAibEGTFTSDKSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：64)，

R ¹-HAibEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：116)，

R ¹-HAibEGTFTSDVSKYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：65)，

R ¹-HAibEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：117)，

R ¹-HAibEGTFTSDVSSYKEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：66)，

R ¹-HAibEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：118)，

R ¹-HAibEGTFTSDVSSYLEKQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：67)，

R ¹-HAibEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：119)，

R ¹-HAibEGTFTSDVSSYLEEQKVKEFIAWLIKAibR-R ²(SEQ?ID?NO：68)，

R ¹-HAibEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAibR-R ²(SEQ?ID?NO：120)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEKIAWLIKAibR-R ²(SEQ?ID?NO：69)，

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAibR-R ²(SEQ?ID?NO：121)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIKWLIKAibR-R ²(SEQ?ID?NO：70)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIK(SH)WLIKAibR-R ²(SEQ?ID?NO：122)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWKIKAibR-R ²(SEQ?ID?NO：71)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWK(SH)IKAibR-R ²(SEQ?ID?NO：123)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK-R ²(SEQ?ID?NO：72)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：124)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK(Ac)AibR-R ²(SEQ?ID?NO：73)，

R ¹-HAibEGTFTSDvSSYLEEQAvKEFIAWLIK (benzoyl) AibR-R ²(SEQ ID NO:74),

R ¹-H (anti--the 3-caproyl) AibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ ID NO:75) and

R ¹-H (3-aminophenyl ethanoyl) AibEGTFTSDVSSYLEEQAVKEFIAWLIK AibR-R ²(SEQ IDNO:76).

73. as each described GA target agent in the claim 48～71, it comprises the peptide that comprises and be selected from the basic homologous sequence of one or more compounds of following compounds:

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGR-R ²(SEQ?ID?NO：32)

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：33)

R ¹-HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：34)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：35)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKAibRK-R ²(SEQ?ID?NO：36)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：37)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK(SH)-R ²(SEQ?ID?NO：38)

R ¹-HAibEGTFTSDVSSYLEGQAAK(SH)EFIAWLVKGR-R ²(SEQ?ID?NO：39)

R ¹-HAibEGTFTSDVSSYGEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：40)

R ¹-HAibEGTFTSDVSSYCEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：41)

R ¹-HAibEGTFTSDVSSYFEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：42)

R ¹-HAibEGTFTSDVSSYYEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：43)

R ¹-HAibEGTFTSDVSSYWEGQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：44)

R ¹-HAibEGTFTSDVSSYLEEQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：45)

R ¹-HAibEGTFTSDVSSYLEDQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：46)

R ¹-HAibEGTFTSDVSSYLEKQAAKEFIAWLVKAibR-R ²(SEQ?ID?NO：47)

R ¹-HAibEGTFTSDVSSYLEGQAVKEFIAWLVKAibR-R ²(SEQ?ID?NO：48)

R ¹-HAibEGTFTSDVSSYLEGQAIKEFIAWLVKAibR-R ²(SEQ?ID?NO：49)

R ¹-HAibEGTFTSDVSSYLEGQALKEFIAWLVKAibR-R ²(SEQ?ID?NO：50)

R ¹-HAibEGTFTSDVSSYLEGQAAREFIAWLVKAibR-R ²(SEQ?ID?NO：51)

R ¹-HAibEGTFTSDVSSYLEGQAAOrnEFIAWLVKAibR-R ²(SEQ?ID?NO：52)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAFLVKAibR-R ²(SEQ?ID?NO：53)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLIKAibR-R ²(SEQ?ID?NO：54)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVRAibR-R ²(SEQ?ID?NO：55)

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVOrnAibR-R ²(SEQ?ID?NO：56)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：57)

R ¹-HAibEGTFTSDVSSYFEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：58)

R ¹-HAibEGTFTSDVSSYYEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：59)

R ¹-HAibEGTFTSDVSSYWEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：60)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIRAibR-R ²(SEQ?ID?NO：61)

R ¹-HAibEGTFTSDVSSYLEEQAVREFIAWLIRAibR-R ²(SEQ?ID?NO：62)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：63)

R ¹-HAibEGTFTSDKSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：64)

R ¹-HAibEGTFTSDK(SH)SSYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：116)

R ¹-HAibEGTFTSDVSKYLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：65)

R ¹-HAibEGTFTSDVSK(SH)YLEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：117)

R ¹-HAibEGTFTSDVSSYKEEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：66)

R ¹-HAibEGTFTSDVSSYK(SH)EEQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：118)

R ¹-HAibEGTFTSDVSSYLEKQAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：67)

R ¹-HAibEGTFTSDVSSYLEK(SH)QAVKEFIAWLIKAibR-R ²(SEQ?ID?NO：119)

R ¹-HAibEGTFTSDVSSYLEEQKVKEFIAWLIKAibR-R ²(SEQ?ID?NO：68)

R ¹-HAibEGTFTSDVSSYLEEQK(SH)VKEFIAWLIKAibR-R ²(SEQ?ID?NO：120)

R ¹-HAibEGTFTSDVSSYLEEQAVKEKIAWLIKAibR-R ²(SEQ?ID?NO：69)

R ¹-HAibEGTFTSDVSSYLEEQAVK(SH)EKIAWLIKAibR-R ²(SEQ?ID?NO：121)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIKWLIKAibR-R ²(SEQ?ID?NO：70)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIK(SH)WLIKAibR-R ²(SEQ?ID?NO：122)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWKIKAibR-R ²(SEQ?ID?NO：71)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWK(SH)IKAibR-R ²(SEQ?ID?NO：123)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK-R ²(SEQ?ID?NO：72)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：124)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK(Ac)AibR-R ²(SEQ?ID?NO：73)

R ¹-H (3-aminophenyl ethanoyl) AibEGTFTSDVSSYLEEQAVKEFIAWLIK AibR-R ²(SEQ ID NO:76)

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIK (benzoyl) AibR-R ²(SEQ ID NO:74)

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-R ²(SEQ?ID?NO：1)，

R ¹-HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：125)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGRK-R ²(SEQ?ID?NO：126)，

R ¹-HAibEGTFTSDVSSYLEGQAAKEFIAWLVKGR-R ²(SEQ?ID?NO：127)，

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibR-R ²(SEQ ID NO:128) and

R ¹-HAibEGTFTSDVSSYLEEQAVKEFIAWLIKAibRPSSGAPPPS-R ²(SEQ?ID?NO：129)。

74. as each described GA target agent in the claim 48～71, it comprises the peptide that comprises and be selected from the basic homologous sequence of one or more compounds of following compounds:

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：2)

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：3)

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：4)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWKKNGGPSSGAPPPS-R ²(SEQ?ID?NO：19)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIKWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：20)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFKEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：21)

R ¹-HAIBEGTFTSDLSKQMEEKAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：25)

R ¹-HAIBEGTFTSDLKKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：29)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGK-R ²(SEQ?ID?NO：30)

R ¹-HAIBEGTFTSDLSKQMEEEAVRKFIEWLKNGGPK-R ²(SEQ?ID?NO：31)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)

R ¹-HAIBEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGK(SH)SSGAPPPS-R ²(SEQ?ID?NO：114)

R ¹-HAIBEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：173)

R ¹-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID?NO：172)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGG-R ²(SEQ?ID?NO：6)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKN-R ²(SEQ?ID?NO：7)

R ¹-HAIBEGTFTSDLSKQLEEEAVRLFIEFLKN-R ²(SEQ?ID?NO：8)

R ¹-HAIBEGTFTSDLSKQLEEEAVRLAIEFLKN-R ²(SEQ?ID?NO：9)

R ¹-HAIBEGTFTSDLSKQLEEEAVRLAIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：10)

R ¹-HAIBEGTFTSDLSKQLEEEAVRLFIEFLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：11)

R ¹-HAIBEGTFTSDLSK(AC)QMEEEAVRLFIEWLK(AC)NGGPSSGAPPPS-R ²?(SEQ?ID

NO：12)

R ¹-HAIBEGTFTSDLSK (benzoyl) QMEEEAVRLFIEWLK (benzoyl) NGGPSSGAPPPS-R ²

(SEQ?ID?NO：13)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：132)

R ¹-HAIBEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID

NO：147)

R ¹-HAIBEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：5)

R ¹-HAIBEGTFTSDLSKKMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：28)

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：115)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(L’)NGGPSSGAPPPS-R ²(SEQ?ID?NO：156)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKKGGPSSGAPPPS-R ²(SEQ?ID?NO：18)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPKSGAPPPS-R ²(SEQ?ID?NO：17)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSKAPPPS-R ²(SEQ?ID?NO：16)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAKPPS-R ²(SEQ?ID?NO：15)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPKS-R ²(SEQ?ID?NO：14)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：157)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：158)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：159)，

R ¹-HAIBEGTFTSDLSKQMEK (L) EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ ID NO:165) and

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：160)。

75. as the agent of the described GA target of claim 74, it comprises the peptide that comprises and be selected from the basic homologous sequence of one or more compounds of following compounds:

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSK-R ²(SEQ?ID?NO：132)，

R ¹-HAIBEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPSK(SH)-R ²(SEQ?ID

NO：147)，

R ¹-HAIBEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：5)，

R ¹-HAIBEGTFTSDLSKKMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：28)，

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：115)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(L’)NGGPSSGAPPPS-R ²(SEQ?ID?NO：156)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKKGGPSSGAPPPS-R ²(SEQ?ID?NO：18)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPKSGAPPPS-R ²(SEQ?ID?NO：17)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSKAPPPS-R ²(SEQ?ID?NO：16)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAKPPS-R ²(SEQ?ID?NO：15)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPKS-R ²(SEQ?ID?NO：14)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：157)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：158)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：159)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：165)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：160)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWK(SH)KNGGPSSGAPPPS-R ²(SEQ?ID?NO：103)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIK(SH)WLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：104)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFK(SH)EWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：105)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEEK(SH)AVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：109)，

R ¹-HAIBEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAIBEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAIBEGTFTSDLK (SH) KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ ID NO:113) and

R ¹-HAIBEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)。

76. as the agent of the described GA target of claim 75, it comprises and comprises the peptide that is selected from following sequence:

R ¹-HAIBEGTFTSDLKKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：29)，

R ¹-HAIBEGTFTSDLK(SH)KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：5)，

R ¹-HAIBEGTFTSDLSKKMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：28)，

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：113)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：115)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(L’)NGGPSSGAPPPS-R ²(SEQ?ID?NO：156)

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKKGGPSSGAPPPS-R ²(SEQ?ID?NO：18)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPKSGAPPPS-R ²(SEQ?ID?NO：17)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSKAPPPS-R ²(SEQ?ID?NO：16)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAKPPS-R ²(SEQ?ID?NO：15)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPKS-R ²(SEQ?ID?NO：14)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：157)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：158)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：159)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：165)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：160)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPK(SH)S-R ²(SEQ?ID?NO：99)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAK(SH)PPS-R ²(SEQ?ID?NO：100)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSK(SH)APPPS-R ²(SEQ?ID?NO：101)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKNGGPK(SH)SGAPPPS-R ²(SEQ?ID?NO：168)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLKK(SH)GGPSSGAPPPS-R ²(SEQ?ID?NO：102)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRLFIEWLK(SH)NGGPSSGAPPPS-R ²(SEQ?ID?NO：170)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(SH)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)，

R ¹-HAIBEGTFTSDLSK(SH)QMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：169)，

R ¹-HAIBEGTFTSDLK (SH) KQMEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ ID NO:113) and

R ¹-HAIBEGTFTSDLSKQMEEEAVRKFIEWLK(SH)NGGPSS-R ²(SEQ?ID?NO：115)。

77. as the agent of the described GA target of claim 76, it comprises and comprises the peptide that is selected from following sequence:

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：22)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：23)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：24)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：26)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：27)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：111)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(L)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：157)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(L)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：158)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(L)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：159)，

R ¹-HAIBEGTFTSDLSKQMEK(L)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：165)，

R ¹-HAIBEGTFTSDLSKQK(L)EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：160)，

R ¹-HAIBEGTFTSDLSKQMEEEAVRK(SH)FIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：106)，

R ¹-HAIBEGTFTSDLSKQMEEEAVK(SH)LFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：107)，

R ¹-HAIBEGTFTSDLSKQMEEEAK(SH)RLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：108)，

R ¹-HAIBEGTFTSDLSKQMEK(SH)EAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：110)，

R ¹-HAIBEGTFTSDLSKQK (SH) EEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ ID NO:111) and

R ¹-HAIBEGTFTSDLSKK(SH)MEEEAVRLFIEWLKNGGPSSGAPPPS-R ²(SEQ?ID?NO：112)。

78. the compound of a following formula:

Wherein-MAb is link to each other with antibody combining site covalently bound.

79. the compound of a following formula:

80. the compound of a following formula:

81. the compound of a following formula:

82. the compound of a following formula:

83. the compound of a following formula:

84. the compound of a following formula:

85. the compound of a following formula:

86. the compound of a following formula:

87. the compound of a following formula:

88. as each described compound in the claim 47～87, wherein said antibody is catalytic antibody.

89. as the described compound of claim 88, wherein said antibody is zymohexase antibody.

90. as each described compound in the claim 47～89, wherein said antibody is full length antibody, Fab, Fab ', F (ab ') ₂, F _v, dsF _v, scF _v, V _H, double-stranded antibody or comprise V from h38c2 _HAnd V _LThe miniantibody in territory.

91. as each described compound in the claim 47～90, wherein said antibody is full length antibody.

92. as each described compound in the claim 47～91, wherein said antibody is the V that comprises from h38c2 _HAnd V _LTerritory and the antibody that is selected from the constant domain of IgG1, IgG2, IgG3 and IgG4.

93. as each described compound in the claim 47～92, wherein said antibody is the h38c2 with variable heavy chain sequence that variable sequence of light chain that SEQ ID NO:79 explained and SEQ ID NO:80 explained.

94. a pharmaceutical composition, described pharmaceutical composition comprise the treatment significant quantity as each described compound in the claim 1～93.

95. as the described pharmaceutical composition of claim 94, what wherein said pharmaceutical composition also comprised the treatment significant quantity is selected from sulfonylurea, biguanides, thiazolidinedione, α glucosidase inhibitor and MAG for compound how.

96. as each described GA target agent in the claim 1～66 or as the application of each described pharmaceutical composition in the claim 94～95 in increasing individual method of glucose level.

97. one kind increases individual method of glucose level, described method comprise with the treatment significant quantity as each described compound in the claim 1～93 or as individuality as described in each described pharmaceutical composition is treated in the claim 94～95.

98. a method of making the GA target compound, described method comprise covalently bound as at least one binding site of each described compound and h38c2IgG1 in the claim 1～93.

99. one kind basic as herein with reference to the accompanying drawings with the described peptide of sequence list.

100. one kind basic as herein with reference to the accompanying drawings with the described compound of sequence list.

101. one kind basic as herein with reference to the accompanying drawings with the described pharmaceutical composition of sequence list.

102. one kind basic as herein with reference to the accompanying drawings with the described method of sequence list.

103. one kind basic as herein with reference to the accompanying drawings with the described application of sequence list.