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Long-acting glucagon-like peptide-1 analogue and application thereof

A technology for glucagon and analogues, applied in the field of glucagon-like peptide-1 analogues, which can solve problems such as poor solubility, easy aggregation of final products, and many cysteine ​​residues

Active Publication Date: 2017-04-05
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the technical solutions involved in these two published patents, there are too many cysteine ​​residues in the molecule, the synthesis is difficult, too many hydrophobic groups are introduced, the final product is easy to aggregate, the solubility is poor, and the quality of the final product is difficult to control The problem

Method used

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  • Long-acting glucagon-like peptide-1 analogue and application thereof
  • Long-acting glucagon-like peptide-1 analogue and application thereof
  • Long-acting glucagon-like peptide-1 analogue and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] A. Preparation of glucagon-like peptide-1 analogs

[0073] 1) Synthesis: adopt Fmoc strategy, use CS 336 peptide synthesizer (CS Bio), press

[0074] Synthesize step by step as follows:

[0075] a) In the presence of an activator system, the Fmoc-Gly-resin is obtained by coupling the resin solid phase carrier and the Fmoc-protected glycine; among them, amino resins are used to synthesize the C-terminal amidated polypeptide, such as RinkAmide AM, Rink Amide, Rink MBHA, etc. .

[0076] b) 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, use for glutamic acid OtBu, Boc for Lysine, Trt for Glutamine, tBu for Tyrosine, Trt or tBu for Serine, OtBu for Aspartic Acid, tBu for Threonine, Trt for Cysteine, Trt for Histidine Trt or Boc protectio...

Embodiment 2

[0083] Evaluation of hypoglycemic effect of glucagon-like peptide-1 analogs represented by SEQ NOs 1-4

[0084] The hypoglycemic effect of the glucagon-like peptide-1 analogs of the present invention was evaluated by glucose tolerance test in normal mice. Methods: Normal mice (purchased from Shanghai Experimental Animal Center, Chinese Academy of Sciences) were randomly divided into 6 groups (model, positive control, test group), 6 mice in each group; the pure product (≥98%) was weighed and prepared into 0.1 mg / ml of the test product solution, each subcutaneous injection of 200 μl in the test group, measuring glucose tolerance in 4, 24, 48, 72, and 96 hours after administration, and the positive control group was given liraglutide (20 μg / only); Inject 200 μl of saline. Glucose tolerance test: Orally administer glucose 2g / kg, measure the blood glucose values ​​at 15, 30, and 60 minutes, and calculate the blood glucose value AUC (mg / dL.min). see results figure 1 .

[0085] T...

Embodiment 3

[0087] Evaluation of hypoglycemic effect of glucagon-like peptide-1 analogs represented by SEQ ID NO 5, 7, 8, 9

[0088] Evaluation method is the same as embodiment 2, the results are shown in figure 2 .

[0089] The results showed that the test sample showed a significant effect of lowering blood sugar in mice with sugar load when administered for 4 hours, and the strength was equivalent to that of the positive control drug. But the positive control medicine hypoglycemic effect disappears after 24hr, and the test sample still shows drug effect to 96hr after the medicine, wherein the hypoglycemic effect of the glucagon-like peptide-1 analog represented by SEQ ID NO7 and 9 Especially notable.

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Abstract

The invention provides a long-acting glucagon-like peptide-1 analogue. The long-acting glucagon-like peptide-1 analogue is characterized in that the polypeptide has a structure shown as a general formula I: Z1-HX8EX10T FTSDV SSYLE X22QAAK EFIX30W LVKX35RG-Z2, wherein, any two residues of X8, X10, X22, X30, X35 are cysteine, Z2 is -H or -HN2; any one residue of X8, X10, X22, X30, X35 is cysteine, and Z2 is a -CG sequence. The glucagon-like peptide-1 analogue expressed by the general formula I always contains two cysteine residues to form an intramolecular disulfide bond, so that rapid degradation of the analogue in vivo is avoided, and the in-vivo half life is obviously prolonged.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a long-acting glucagon-like peptide-1 analogue and its application. Background technique [0002] Glucagon-like peptide-1 (GLP-1) is a gut-derived hormone synthesized primarily in L cells of the terminal jejunum, 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 and promote the proliferation of islet β-cells, which can be reversed Disease progression. However, the plasma half-life of natural GLP-1 is only 1-2 minutes, and its metabolic instability limits its application as a dr...

Claims

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Application Information

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IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04A61P25/28
CPCA61K38/00C07K14/605
Inventor 韩英梅赵娜夏王玉丽
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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