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A polyethylene glycol-modified glucagon-like peptide-1 analogue

A technology of glucagon and polyethylene glycol, which is applied in the field of glucagon-like peptide-1 analogues, can solve problems such as drug resistance that cannot be solved, and achieve improved clinical application compliance, good metabolic stability, The effect of prolonging the half-life in vivo

Active Publication Date: 2020-04-07
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Existing patent technology (CN1372570A, CN101125207A etc.) discloses the polyethylene glycol modification technology of Exendin-4, although these existing technologies can prolong the in vivo half-life of Exendin-4, can reach long-acting, but these conjugates end up All of them produce drug effects by releasing free Exendin-4 in the body, and the immunogenicity of Exendin-4 itself brings about the production of antibodies (45% of the people who took the drug for 30 weeks produced antibodies) and other drug resistance still cannot be resolved

Method used

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  • A polyethylene glycol-modified glucagon-like peptide-1 analogue
  • A polyethylene glycol-modified glucagon-like peptide-1 analogue
  • A polyethylene glycol-modified glucagon-like peptide-1 analogue

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Embodiment 1

[0060] The present invention will be further described below in conjunction with specific examples. This embodiment is only for explaining the present invention, and does not limit the content of the present invention in any way. For a better understanding of the present invention, see Table 1 for the abbreviations and Chinese names of the reagents used.

[0061] Table 1 Reagent abbreviation and Chinese name comparison

[0062]

[0063] Example 1

[0064] A. Preparation of glucagon-like peptide-1 analogs

[0065] 1) Synthesis: Using the Fmoc strategy, use the CS 336 peptide synthesizer (CS Bio) to synthesize step by step according to the following steps:

[0066] a) In the presence of an activator system, the Fmoc-amino acid-resin is obtained by coupling the resin solid phase carrier and the Fmoc-protected C-terminal amino acid; wherein, the synthesis of the C-terminal amidated polypeptide uses an amino resin, such as Rink Amide AM, Rink Amide , Rink MBHA et al.

[0...

Embodiment 2

[0072] Linear monomethyl PEG (21000 Daltons) modified SEQ ID NO:1

[0073] 1) Ligation: The polypeptide of SEQ ID NO:1 was dissolved in 50 mM sodium phosphate buffer solution at pH 6 containing 5 mM EDTA at a concentration of 2 mg / mL. Add 1.2-1.5 times molar amount of solid PEG-maleimide, stir to dissolve, and react at room temperature for 2 hours. The reaction was monitored by HPLC, terminated with 5 mM β-mercaptoethanol, and purified at room temperature for 30 min.

[0074] 2) Purification: Preparative ion-exchange column chromatography was used, filled with SP SepharoseHP, and eluted with a linear gradient of 0-500mM sodium chloride solution. The effluent was detected by HPLC and SDS-electrophoresis, and the PEG-polypeptide fraction was collected, concentrated by ultrafiltration or desalted with Sephadex G-25, etc., and freeze-dried.

[0075] The purity of the obtained PEG-modified polypeptide was tested by RP-HPLC, and the molecular weight was determined by MALDI-TOF.

Embodiment 3

[0077] Linear monomethyl PEG (30000 Daltons) modified SEQ ID NO:8

[0078] According to the method of Example 2, linear monomethyl PEG (30000 Daltons) modified SEQ ID NO: 8 and the following PEG conjugates of glucagon-like peptide-1 analogs were prepared.

[0079] Linear monomethoxy PEG (45000 Daltons) modified SEQ ID NO:7

[0080] Linear monomethoxy PEG (43000 Daltons) modified SEQ ID NO:8

[0081] Linear monomethoxy PEG (45000 Daltons) modified SEQ ID NO:9

[0082] Linear monomethoxy PEG (41000 Daltons) modified SEQ ID NO:10

[0083] Linear monomethoxy PEG (42000 Daltons) modified SEQ ID NO:11

[0084] Linear monomethoxy PEG (35000 Daltons) modified SEQ ID NO:13

[0085] Linear monomethoxy PEG (42000 Daltons) modified SEQ ID NO:14

[0086] Linear monomethoxy PEG (22000 Daltons) modified SEQ ID NO:16

[0087] Linear monomethoxy PEG (45000 Daltons) modified SEQ ID NO:18

[0088] Linear monomethoxy PEG (46000 Daltons) modified SEQ ID NO:19

[0089] Linear monomethoxy PEG ...

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Abstract

The invention provides a GLP-1 (glucagon-like peptide-1) analogue modified with PEG (polyethylene glycol). The GLP-1analogue has an amino acid sequence shown in SEQ ID NO: 1-19, and the cysteine residue of the amino acid sequence is modified with a PEG group. The invention further provides an application of the analogue or analogue composition in preparation of drugs for treating diabetes, obesity and Alzheimer's disease. The polypeptide has better metabolism stability, has remarkably prolonged in-vivo half-life period, solves the problem that the half-life period of natural GLP-1 is short, can substantially improve the clinical application compliance and has higher application value.

Description

[0001] This application claims the priority of the invention patent application titled "a polyethylene glycol-modified glucagon-like peptide-1 analogue" submitted on April 6, 2016, with application number 20161021111440. technical field [0002] The invention belongs to the technical field of medicine, and in particular relates to a polyethylene glycol-modified glucagon-like peptide-1 analogue and its medical use. Background technique [0003] Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone synthesized primarily in L cells of the terminal empty field, ileum, and colon, and released into circulation in response to a meal. GLP-1(7-36,7-37), the major active form of GLP-1 in the systemic circulation, controls blood glucose through complex mechanisms including secretion of insulin and glucagon, gastric emptying, and regulation of peripheral insulin. The hypoglycemic effect of GLP-1(7-36,7-37) is glucose-dependent, can avoid hypoglycemia, and can inhibit the apoptosis of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/04A61P3/10A61P25/28A61K47/60
CPCA61K38/00C07K14/605
Inventor 韩英梅赵娜夏王玉丽夏广萍孔维苓
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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