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GLP-1 analogs, preparation method thereof application thereof

A technology of GLP-1 and analogues, which is applied in peptide preparation methods, chemical instruments and methods, drug combinations, etc., can solve problems such as failure to meet clinical standards, inconvenient clinical use, and short half-life of liraglutide

Active Publication Date: 2012-08-22
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the serum half-life of GLP-1(7-37) is only 3-5 minutes, and multiple injections per day are very inconvenient in clinical use
[0003] At present, many studies have adopted GLP-1 analog fusion protein technology to solve the retention time of GLP-1 analog in vivo (CN90101167.3, CN200710018734.2, CN200410054397.9, CN01820232.2, CN200380110152.7, CN200510039265.3 , CN200610127237.1, CN200910009642.7), however, there is still a great distance between the existing technology and the ideal clinical goal, and generally have not reached the clinical standard. Recently, the liraglutide produced by Novo Norisk is a GLP-1 analog , which modified GLP-1 with palmitic acid, and was launched in the United States in 2009
However, liraglutide also has the problem of short half-life, and its dosage form still needs daily injections
[0004]Therefore, there is currently a need for methods that address the short in vivo half-life of GLP-1

Method used

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  • GLP-1 analogs, preparation method thereof application thereof
  • GLP-1 analogs, preparation method thereof application thereof
  • GLP-1 analogs, preparation method thereof application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] Example 1: Solid Phase Synthesis of Polypeptides

[0157] The synthesis of the polypeptides of the present invention was carried out using the solid-phase polypeptide synthesis method of the Fmoc strategy, using a CS 336X instrument produced by CSBio. The method of synthesis was carried out according to the manufacturer's instrument instructions.

[0158] The prepared polypeptide was purified by HPLC C18 semi-preparative column, and the mobile phase was acetonitrile. After desalting and freeze-drying, polypeptide freeze-dried powder is obtained. The polypeptides contained in this patent all contain disulfide bonds, and ammonium bicarbonate or other reducing agents are used to form the disulfide bonds in the polypeptides.

Embodiment 2

[0159] Example 2: Hypoglycemic function associated with GLP-1 analogs (formula II)

[0160] In this example, the polypeptides used are as follows:

[0161] SEQ ID NO 1: 7 HAEGT FTSCV SSYLE GQAAK EFIAW LVKGR G 37 GGGGGC GGG

[0162] SEQ ID NO 2: 7 HAEGT FTSCV SSYLE GQAAK EFIAW LVKGR G 37 GGGGGGGGGGC GGG

[0163] SEQ ID NO 3: 7 HAEGT FTSCV SSYLE GQAAK EFIAW LVKGR G 37 GGGGGGGGGGGGGGGC GGG

[0164] SEQ ID NO 4: 7 HAEGT FTSCV SSYLE GQAAK EFIAW LVKGR G 37 GGGGGC GGGGG G

[0165] SEQ ID NO 5: 7 HAEGT FTSCV SSYLE GQAAK EFIAW LVKGR G 37 GGGGGC GGGGG GGGG

[0166] SEQ ID NO 6: 7 HAEGT FTSCV SSYLE GQAAK EFIAW LVKGR G 37 GGGGGGGGGGC GGGGG G

[0167] SEQ ID NO 7: 7 HAEGT FTSCV SSYLE GQAAK EFIAW LVKGR G 37 GGGGGGGGGGC GGGGG GGGG

[0168] SEQ ID NO 8: 7 HAEGT FTSCV SSYLE GQAAK EFIAW LVKGR G 37 GGGGGGGGGGGGGGGC GGGGG G

[0169] SEQ ID NO 9: 7 HAEGT FTSCV SSYLE GQAAK EFIAW LVKGR G 37 GGGGGGGGGGGGGGGC GGGGG GGGG

[0170] SEQ ID NO 10: 7 HAEGT FTSCV SSYLE GQAAK EFIAW...

Embodiment 3

[0189] Example 3: Hypoglycemic function associated with GLP-1 analogs (formula III).

[0190]In this example, the polypeptides used are as follows:

[0191] SEQ ID NO 28: 7 HAEGT FTSDV SSYLE GQAAK EFICW LVKGR G 37 G CGGGGG GGGGG

[0192] SEQ ID NO 29: 7 HAEGT FTSDV SSYLE GQAAK EFICW LVKGR G 37 G CGGGGG GGGGGGGGGG

[0193] SEQ ID NO 30: 7 HAEGT FTSDV SSYLE GQAAK EFICW LVKGR G 37 G CGGGGG GGGGGGGGGGGGGGGGGGGG

[0194] SEQ ID NO 31: 7 HAEGT FTSDV SSYLE GQAAK EFICW LVKGR G 37 GG CGGGGG GGGGG

[0195] SEQ ID NO 32: 7 HAEGT FTSDV SSYLE GQAAK EFICW LVKGR G 37 GG CGGGGG GGGGGGGGGG

[0196] SEQ ID NO 33: 7 HAEGT FTSDV SSYLE GQAAK EFICW LVKGR G 37 GG CGGGGG GGGGGGGGGGGGGGG

[0197] SEQ ID NO 34: 7 HAEGT FTSDV SSYLE GQAAK EFICW LVKGRG 37 GGGGG C GGGGG GGGGG

[0198] SEQ ID NO 35: 7 HAEGT FTSDV SSYLE GQAAK EFICW LVKGRG 37 GGGGG C GGGGG GGGGGGGGGG

[0199] SEQ ID NO 36: 7 HAEGT FTSDV SSYLE GQAAK EFICW LVKGRG 37 GGGGG C GGGGG GGGGGGGGGGGGGGG

[0200] SEQ ID NO 37:...

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Abstract

The invention discloses GLP-1 analogs which have the following general formula I: 7HAEX10T FTSX15V SSYLE X22QAAK EFIX30W LX33KGR G37n1X1C n2X2, wherein X10 is glycine or cysteine, X15 is aspartic acid or cysteine, X22 is glycine or cysteine, X30 is alanine or cysteine, X33 is valine or cysteine, and at least one of X10, X15, X22, X30 and X33 is cysteine; n1X1 represents n X1s, n=3-30, and X1 is glycine, alanine or valine; n2X2 represents n X2s, n=3-30, and X2 is glycine, alanine or valine; and the two cysteines contained in the general formula I respectively form a disulfide bond. The GLP-1 analogs can effectively increase the blood half life of GLP-1, can overcome the actual state that the GLP-1 analogs can not be used clinically due to short half life, and has wide application prospects in the field of therapeutic drugs for diabetes and obesity. The invention also discloses a preparation method of the GLP-1 analogs and application thereof.

Description

technical field [0001] The present invention relates to the field of medicines related to diabetes, in particular, the present invention relates to a GLP-1 analog with prolonged in vivo half-life of glucagon-like peptides (GLP-1). The invention also relates to the preparation method of the GLP-1 analog and its application in the preparation of diabetes medicine. Background technique [0002] The GLP-1 (glucagon-likepeptide-1, hereinafter referred to as: GLP-1) involved in the present invention is a polypeptide consisting of 37 amino acids mainly secreted by small intestinal L cells, and its active form is GLP-1 (7-37) OH and GLP-1(7-36)NH2 (Mojsov S, J Clin Invest. 1987 Feb;79(2):616-9). GLP-1 significantly reduces blood sugar after meals, stimulates insulin production, and has a certain weight loss effect, without causing hypoglycemia (Drucker D J, Diabetes. 1998 Feb; 47(2): 159-69 ). Recent studies have also shown that GLP-1 has a role in pancreatic regeneration (Drucke...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/06C07K1/04A61K38/26A61P3/04A61P3/10
CPCA61K38/00A61P3/04A61P3/10C07K14/605
Inventor 龚珉徐为人付刚王玉丽汤立达郑学敏孟凡翠李心任晓文
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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