Glucagon-like peptide-1 analog and uses thereof

A technology for glucagon and analogues, which is applied in the field of glucagon-like peptide-1 analogues and their medical applications, which can solve the problems of affecting drug efficacy, weakening the binding effect of peptides and receptors, and limiting drug loading of molecules To achieve the effect of reducing dosage, improving clinical compliance, and strong hypoglycemic activity

Active Publication Date: 2019-02-26
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally speaking, high molecular weight (≥20KD) PEG modification is more conducive to prolonging the in vivo half-life of polypeptide or protein drugs, but usually only one active end group of each PEG molecule is coupled to the precursor active molecule, and the drug loading capacity of the molecule is limited. Moreover, the binding effect between the polypeptide after polymer modification and the receptor is usually weakened, which affects the efficacy of the drug. Therefore, the activity intensity of the precursor polypeptide is an important factor in determining the druggability of the final modified product.

Method used

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  • Glucagon-like peptide-1 analog and uses thereof
  • Glucagon-like peptide-1 analog and uses thereof
  • Glucagon-like peptide-1 analog and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Example 1 Preparation of Glucagon-Like Peptide-1 Analogue Precursor Polypeptide

[0102] The precursor polypeptide shown in general formula I is prepared by the following steps

[0103] 1) Synthesis: Using the Fmoc strategy, use the CS 336 peptide synthesizer (CS Bio) to synthesize step by step according to the following steps:

[0104] 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.

[0105] b) Extension of the peptide chain: Connect amino acids in accordance with the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain a peptide-resin conjugate with N-terminal and side chain protection; take the following protection measures for amino acids with side chains: use Boc for tryptophan , OtB...

Embodiment 2

[0165] Example 2 Solubility and Stability Experiments of Glucagon-Like Peptide-1 Analogue Precursor Polypeptide

[0166] The preferred polypeptides provided by the present invention have been evaluated for solubility and solution stability, and at the same time compared with the polypeptide sequence (Gly2, Cys37GLP-1 (7-37): SEQ ID NO: 57HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRC with only a simple transformation of the original sequence of GLP-1 ) and the sequence involved in the patent (CN201610211144.0) (Gly2, Aib35, Ala38, Cys39GLP-1(7-37):SEQ ID NO:58

[0167] HGEGTFTSDVSSYLEGQAAKEFIAWLVKAibRGAC) were compared and found that the structural transformation in the technical solution of the present invention effectively solved the solubility and solution stability of the precursor polypeptide.

[0168] sample:

[0169] SEQ ID NO:57, SEQ ID NO:58,

[0170] SEQ ID NO:1, 9, 11, 15, 17, 24, self-made, purity ≥ 98%.

[0171] Solubility:

[0172] Prepare the above sample solution with a...

Embodiment 3

[0181] Example 3 Evaluation of the Hypoglycemic Effect of the Precursor Polypeptide of Glucagon-Like Peptide-1 Analogue

[0182] The hypoglycemic effect of some polypeptides provided by the present invention was evaluated by using a normal mouse glucose load model.

[0183] Samples tested:

[0184] SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:4, 9, 11, 15, 17, 19 self-made, purity ≥ 98%

[0185] method:

[0186] Animals (n=8) fasted overnight before the experiment, subcutaneously injected normal saline (10mL / kg) as the control group; subcutaneously injected a single liraglutide (200 μg / kg) as the positive control drug group; measured blood glucose before administration , give positive drug and test sample (200μg / kg), intraperitoneal injection of glucose (4.5g / kg) at the same time and 2 and 4 hours after the administration, take blood from the tip of the tail to measure the blood glucose value 30min after the sugar is given, and calculate relative to The blood sugar suppression r...

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Abstract

The present invention provides a precursor polypeptide or a pharmaceutically acceptable salt of a glucagon-like peptide-1 analogue, wherein the precursor polypeptide has an amino acid sequence represented by the following general formula I HX1X2GTFTSDVSSYLEEX3AAX4EFIX5WLVKX6X7X8X9, and X1, X2, X3, X4, X5, X6, X7, X8 and X9 represent arbitrary amino acids. The present invention further provides a glucagon-like peptide-1 analog or a pharmaceutically acceptable salt thereof. According to the present invention, the glucagon-like peptide-1 analog is obtained by conjugating a polypeptide optimized based on an endogenous GLP-1 (7-36/37) sequence and polyethylene glycol having a specific structure, has strong blood glucose lowering activity so as to reduce the dosage, and has significantly-prolonged half-life in vivo so as to be expected to improve clinical compliance; and the precursor polypeptide and the endogenous GLP-1 (7-36/37) are highly homologous in the sequence so as to reduce the immunogenicity, such that the precursor polypeptide has good potential in the drug development application.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a glucagon-like peptide-1 analogue and its medical application. Background technique [0002] 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) is the main active form of GLP-1 in the systemic circulation and 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 islet β-cells, promote the proliferation of islet β-cells, and can reverse the disease develop. However, the plasma half-life of natural GLP-1 is only 1-2 minutes, and its metabolic instability limits its application as a drug. [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04A61P3/00
CPCA61K38/00C07K14/605
Inventor 韩英梅赵娜夏王玉丽夏广萍刘冰妮
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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