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Modified glucagon sample peptide-1analogue and modifying matter, and uses thereof

A technology for glucagon and analogs, applied in the field of novel glucagon-like peptide-1 analogs and their modifications, which can solve the problems of long pharmacological action time, lack of hypoglycemic effect and stability , to achieve stability and increase in vivo action time, superior biological characteristics, and the effect of promoting insulin secretion and lowering blood sugar

Inactive Publication Date: 2009-02-18
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0027] However, none of the above-mentioned changes in the molecular structure of GLP-1 have significantly improved the hypoglycemic effect and stability compared with native GLP-1, and it is still necessary to develop effective GLP-1 analogs, which not only show anti-inflammatory effects on proteins / peptides such as DPP-IV Hydrolytic enzymes are resistant to degradation and should have a longer duration of pharmacological action

Method used

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  • Modified glucagon sample peptide-1analogue and modifying matter, and uses thereof
  • Modified glucagon sample peptide-1analogue and modifying matter, and uses thereof
  • Modified glucagon sample peptide-1analogue and modifying matter, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1 Chemical synthesis of glucagon-like peptide-1 analogues

[0064] The analogs of the present invention can be prepared by conventional solid-phase peptide synthesis methods to prepare the GLP-1 analogs involved in the present invention, and the specific operation is entrusted to Shanghai Jier Biochemical Company to complete.

[0065] One of the polypeptides of the present invention is synthesized by solid-phase synthesis, and the sequence is:

[0066] SEQ NO 1: KHAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2

[0067] Other peptide synthesis methods are similar.

[0068] The synthesis process adopts Fmoc synthesis method, and Rink-Amide-MBHA Resin is selected for synthesis. The synthesis steps are as follows:

[0069] (1) 16 kinds of Fmoc-amino acid raw materials with side chain protecting groups

[0070] (2) Solid phase synthesis

[0071] (3) Remove the side chain protecting group

[0072] (4) HPLC purification

[0073] (5) Freeze drying

[0074] (6) GLP-1 analogs.

Embodiment 2

[0075] Example 2 In vitro activity determination of GLP-1 analogs

[0076] Test sample:

[0077] SEQ NO 1: KHAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2

[0078] SEQ NO 2: KHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG

[0079] SEQ NO 3: KHAEGTFTSD SSYLEGQAAKEFIAWLVKGR-NH 2

[0080] SEQ NO 4: KHAEGTFTSDV SYLEGQAAKEFIAWLVKGR-NH 2

[0081] SEQ NO 5: KHAEGTFTSDVSS LEGQAAKEFIAWLVKGR-NH 2

[0082] SEQ NO 6: KHAEGTFTSDVSSYLEGQAAK FIAWLVKGR-NH 2

[0083] SEQ NO 7: KHAEGTFTSDVSSYLEGQAAKEF AWLVKGR-NH 2

[0084] SEQ NO 8: KHAEGTFTSDVSSYLEGQAAKEFIA LVKGR-NH 2

[0085]GLP-1(7-36) amide is a positive control: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2

[0086] experiment method:

[0087] Inoculate CHO / EGFP / GLP-1R cells in a 96-well plate with a density of 2×10 4 RPMI-1640 complete culture medium containing 100mg / L Zeocin was cultured for 48 hours and then the culture medium was removed, and the above-mentioned GLP-1 analogues (SEQ NO 1, SEQ NO. 1 and SEQ ID NO. 1) were serially diluted with RPMI-1640 basic me...

Embodiment 3

[0090] Example 3 In vitro anti-DPP-IV degradation determination of GLP-1 analogs

[0091] Test sample:

[0092] SEQ NO 1: KHAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2

[0093] SEQ NO 2: KHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG

[0094] SEQ NO 3: KHAEGTFTSD SSYLEGQAAKEFIAWLVKGR-NH 2

[0095] SEQ NO 4: KHAEGTFTSDV SYLEGQAAKEFIAWLVKGR-NH 2

[0096] SEQ NO 5: KHAEGTFTSDVSS LEGQAAKEFIAWLVKGR-NH 2

[0097] SEQ NO 6: KHAEGTFTSDVSSYLEGQAAK FX 29 AX 31 LVKGR

[0098] SEQ NO 7: KHAEGTFTSDVSSYLEGQAAKE AWLVKGR-NH 2

[0099] SEQ NO 8: KHAEGTFTSDVSSYLEGQAAKEFIA LVKGR-NH 2

[0100] GLP-1(7-36) amide is a positive control: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2

[0101] experiment method:

[0102] Take 20 g of fresh pig kidney cortex tissue and chop it, add 0.25 mol / L sucrose solution at 20% (w / v), and homogenize with a homogenizer. The homogenate was centrifuged at 8,000 rpm for 15 min, and then the supernatant was centrifuged at 15,000 rpm for 2 hours. The precipitate was dissolved in 0.1 mol / L Tris / ...

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Abstract

The present invention relates to a mutant polypeptide of glucagon-like peptide-1 (GLP-1) and a modified compound thereof. In particular, a lysine is added in front of the end N of the glucagon-like peptide-1 to form the mutant polypeptide, and the glucagon-like peptide-1 includes natural GLP-1(7-36)amide or GLP-1(7-37) and a partial amino acid-subsituted derivative. Not only do the GLP-1 mutant polypeptide and the modified compound thereof show the effects of promoting insulin secretion and lowering blood sugar, but also, compared with the natural GLP-1, the stability and internal action time of the GLP-1 mutant polypeptide and the modified compound thereof are notably increased in respect to proteolytic enzyme, and the GLP-1 mutant polypeptide and the modified compound thereof can be used for the preparation of drugs treating diabetes or adiposity.

Description

【Technical Field】: [0001] The present invention relates to a new class of glucagon-like peptide-1 (GLP-1) analogs and their modifications. Specifically, the present invention relates to the transformation and modification of GLP-1 polypeptides. Such peptides not only show the superior biological properties of natural GLP-1, but also have significantly improved stability of proteolytic enzymes and in vivo action time compared with natural GLP-1, and can be used for the treatment of diabetes and obesity. Of adjuvant therapy. 【Background technique】: [0002] Diabetes (Diabetes Mellitus, DM) is a disease that seriously endangers human health. The number of patients is rapidly increasing with the improvement of living standards, the aging of the population and the advancement of diagnostic technology. Diabetic patients are divided into two types, namely insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes). Among them, type 2 diabetes accoun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04
Inventor 白钢高智慧陈家琪张奇白芳
Owner NANKAI UNIV
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