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Glucagon-like peptide-1 (GLP-1) analogue monomer and dimer, preparation method therefor and application thereof

A technology of glucagon and analogues, applied in GLP-1 dimer, the application field of medicine, can solve the problems of short half-life of liraglutide, short half-life of GLP-1, inconvenient clinical use, etc.

Active Publication Date: 2012-10-10
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, it is currently necessary to solve the problem of the short half-life of GLP-1 in vivo

Method used

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  • Glucagon-like peptide-1 (GLP-1) analogue monomer and dimer, preparation method therefor and application thereof
  • Glucagon-like peptide-1 (GLP-1) analogue monomer and dimer, preparation method therefor and application thereof
  • Glucagon-like peptide-1 (GLP-1) analogue monomer and dimer, preparation method therefor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: the solid-phase synthesis of polypeptide

[0069] Using the solid-phase peptide synthesis method of the Fmoc strategy, the CS 336X instrument produced by CSBio Company was used to synthesize the cysteine-containing GLP-1 monomer of the present invention. The method of synthesis was carried out according to the manufacturer's instruction manual.

[0070] The prepared GLP-1 monomer containing cysteine ​​was purified using an HPLC C18 semi-preparative column, and the mobile phase was acetonitrile. The dry powder of GLP-1 monomer containing cysteine ​​is obtained by desalting and freeze-drying. The disulfide bonds in this example are formed by ammonium bicarbonate or other reducing agents.

Embodiment 2

[0071] Example 2: GLP-1 dimer (formed from SEQ ID NO 1 and other GLP-1 monomers) related hypoglycemic function

[0072] In this embodiment, the GLP-1 dimer used is as follows:

[0073] The GLP-1 monomers containing cysteine ​​are SEQ ID NO 1 and the GLP-1 dimer of SEQ ID NO 1, respectively;

[0074] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 1 and SEQ ID NO 2, respectively;

[0075] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 1 and SEQ ID NO 3;

[0076] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 1 and SEQ ID NO 4;

[0077] GLP-1 monomers containing cysteine ​​are dimers of SEQ ID NO 1 and SEQ ID NO 5;

[0078] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 1 and SEQ ID NO 6;

[0079] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 1 and SEQ ID NO 7, respectively.

[0080] Dissolve 1 mg of each of the above-mentioned dimers (7 species in total) in 1 ml of norma...

Embodiment 3

[0082] Example 3: GLP-1 dimer (formed by SEQ ID NO 2 and other GLP-1 monomers) related hypoglycemic function.

[0083] In this embodiment, the GLP-1 dimer used is as follows:

[0084] The GLP-1 monomers containing cysteine ​​are SEQ ID NO 2 and the GLP-1 dimer of SEQ ID NO 2;

[0085] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 2 and SEQ ID NO 3;

[0086] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 2 and SEQ ID NO 4, respectively;

[0087] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 2 and SEQ ID NO 5;

[0088] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 2 and SEQ ID NO 6;

[0089] GLP-1 monomers containing cysteine ​​are GLP-1 dimers of SEQ ID NO 2 and SEQ ID NO 7, respectively.

[0090] Dissolve 1 mg of each of the above-mentioned dimers (a total of 6 species) in 1 ml of normal saline, and inject them subcutaneously into mice (200 μl / mouse, 6 / group, purchased from Shanghai Expe...

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Abstract

The invention provides a GLP-1 dimer, a preparation method therefore and an application thereof. The GLP-1 dimer is formed by two GLP-1 monomers containing cysteine connected via a disulfide bond formed by cysteine. The general formula of the GLP-1 monomer containing cysteine is 7HAEX10T FTSX15V SSYLE X22X23AAKEFIX30W LX33KGR G37; wherein X10 is aglycine or cysteine, X15 is aspartic acid or cysteine, X22 is glycine or cysteine, X23 is leucine or cysteine, X30 is alanine or cysteine, X33 is valine or cysteine, and only one among X10, X15, X22, X23, X30 and X33 is cysteine. The GLP-1 dimer in the invention has an in vivo half-life of more than 8 to 96 hours, thus greatly facilitating clinical promotion and application.

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 dimer with prolonged in vivo half-life of glucagon-like peptides (GLP-1). The present invention also relates to the preparation method of the GLP-1 dimer and its application in the preparation of medicines for treating diabetes, and treating and / or preventing obesity. Background technique [0002] Glucagon-like peptide-1 (hereinafter referred to as: GLP-1) is a polypeptide composed 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)NH 2 (Mojsov S, J Clin Invest. 1987 Feb;79(2):616-9). GLP-1 can significantly reduce the blood sugar after meals, can stimulate the production of insulin, and can also play a certain role in weight loss, and will not cause hypoglycemia (Drucker D J, Diabetes.1998 Feb; 47 (2): 159-69 ). Recent studies have also shown that GLP-1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/04A61K38/26A61P3/04A61P3/10
CPCA61K38/26C07K14/605A61K38/00A61P3/04A61P3/10
Inventor 龚珉徐为人王玉丽付刚汤立达任晓文
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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