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GLP-1 derivative

A technology of GLP-1 and its derivatives, which is applied in the field of bioengineering, can solve the problems of loss of activity, etc., and achieve the effect of simple production method, low cost and mature technology

Inactive Publication Date: 2009-06-24
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the derivatives prepared by the background technology also have the following disadvantages: for example, the amino acid at position 2 is still easily degraded by dipeptidyl peptidase IV and loses its activity in vivo

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The GLP-1 derivative of the present invention is synthesized by a solid-phase chemical synthesis method. The molecular structure of the derivative is: aGLP-1(7-36), namely Seq ID No. 2, where Xaa2=D-Ala, Xaa20=Ser, Xaa28=Ala, Xaa30=Cys, and the C-terminal of Cys is amide-NH2, operation steps:

[0038] 1. A total of 16 amino acid monomers with protective groups are used, they are: Fmoc-L-Ala-OH, Fmoc-D-Ala-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Val -OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Gly-OH, Fmoc-L-Leu-OH, Fmoc-L-Thr(tBu)- OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Phe-OH, Fmoc-L-Ser(tBu)-OH, Fmoc-L-Ile-OH, Fnoc-L-Asp(OtBu)-OH , Fmoc-L-Trp-OH, Fmoc-L-Cys(Trt)-OH, where the abbreviation means:

[0039] Fmoc: 9—fluorenyl methoxycarbonyl

[0040] Trt: Trityl, namely trityl

[0041] OtBu: tert-butyl ester

[0042] tBU: tert-butyl, namely tert-butyl;

[0043] 2. Equipment and reagents needed

[0044] Instrument: SYMPHONY 12-channel peptide synthesizer, model: SYMPHONY, American prod...

Embodiment 2

[0063] Example 2 The GLP-1 derivative of the present invention is synthesized by solid-phase chemical synthesis. The molecular structure of the derivative is aGLP-1(7-37), namely Seq ID No. 3, where Xaa2=D-Ala, Xaa20= Ser, Xaa28=Ala, Xaa30=Gly, Xaa31=Cys, and the C-terminal of Cys is carboxy-OH. In this example, Wang’s resin is selected.

[0064] In the first step of the operation procedure, weigh 1mmol of the amino acid monomer with the protective group into a bottle, according to the amino acid sequence of the GLP-1 derivative, that is, Seq ID No.3, arranged in SYMPHONY from the C-end to the N-end Type 12-channel peptide synthesizer:

[0065] Fmoc-L-Cys(Trt)-OH, Fmoc-L-Gly-OH, Fmoc-L-Gly-OH, Fmoc-L-Ala-OH, Fmoc-L-Val-OH, Fmoc-L-Leu-OH , Fmoc-L-Trp-OH, Fmoc-L-Ala-OH, Fmoc-L-Ile-OH, Fmoc-L-Phe-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-L-Ser( tBu)-OH, Fmoc-L-Ala-OH, Fmoc-L-Ala-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Gly-OH, Fmoc-L-Glu(OtBu)-OH , Fmoc-L-Leu-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Ser(tBu)-OH, Fm...

Embodiment 3

[0067] Example 3 The GLP-1 derivative of the present invention is prepared by a solid-phase chemical synthesis method. The molecular structure of the derivative is aGLP-1(7-38), namely Seq ID No. 4, where Xaa2=Ser, Xaa20=Gln, Xaa28=Asp, Xaa30=Gly, Xaa31=Gly, Xaa32=Cys, and the C-terminal of Cys is carboxy-OH. In this example, Wang’s resin is selected.

[0068] In the first step of the procedure, weigh 1mmol of the amino acid monomer with the protective group into a bottle, and arrange it in SYMPHONY from the C-terminal to the N-terminal according to the amino acid sequence of the GLP-1 derivative, that is, Seq ID No.4. Type 12-channel peptide synthesizer:

[0069]Fmoc-L-Cys(Trt)-OH, Fmoc-L-Gly-OH, Fmoc-L-Gly-OH, Fmoc-L-Gly-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc-L- Val-OH, Fmoc-L-Leu-OH, Fmoc-L-Trp-OH, Fmoc-L-Ala-OH, Fmoc-L-Ile-OH, Fmoc-L-Phe-OH, Fmoc-L-Glu( OtBu)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Ala-OH, Fmoc-L-Ala-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Gly-OH , Fmoc-L-Glu(OtBu)-OH, Fmoc-L-Leu-OH, Fm...

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Abstract

The invention discloses a GLP-1 derivant, which is characterized in that the molecular structural formula of the derivant is any one of the following structural formulas: aGLP-1(7-36), namely Seq ID No.2; aGLP-1(7-37), namely Seq ID No.3; or aGLP-1(7-38), namely Seq ID No.4. The invention also discloses a preparation method for the GLP-1 derivant by solid phase chemosynthesis and the application in preparing drugs for curing diabetes.

Description

Technical field [0001] The invention relates to a human glucagon-like peptide-1 (GLP-1 derivative) with human glucagon-like peptide-1 (Glucagon-like Peptide 1, GLP-1) activity and its preparation and application , Belongs to the field of bioengineering technology. Background technique [0002] Human glucagon-like peptide-1 (GLP-1) is a 31-amino acid polypeptide hormone mainly secreted by L cells in the distal ileum, colon and rectum. Insulin releases, stimulates the release of somatostatin and inhibits glucagon. It is a polypeptide drug for the treatment of diabetes, especially type II diabetes. It has a wide range of social benefits and huge economic benefits. [0003] However, GLP-1 is easily degraded by DipeptidylPep tidase IV (DPP IV) to remove N-terminal His in the body. 7 -Ala 8 -Residues of inactive GLP-1(9-37) or GLP-1(9-36)-NH 2 . The half-life of intravenous GLP-1 in the body is only 3 to 5 minutes, which limits the clinical application of GLP-1. [0004] One of the cur...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/20C07K1/06C07K1/04A61K38/26A61P3/10
CPCY02P20/55
Inventor 黄静金丽金明飞吴自荣刘雯
Owner EAST CHINA NORMAL UNIVERSITY
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