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GLP-1 derivative and preparation method and application thereof

A technology of GLP-1 and derivatives, applied in chemical instruments and methods, drug combinations, pharmaceutical formulations, etc., can solve problems such as difficulty in maintaining secondary structure and instability of GLP-1

Inactive Publication Date: 2015-05-13
NANJING UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the GLP-1 produced by the human body is very unstable, and it is quickly degraded and inactivated by DPP-4 in the body, with a half-life of less than 2 minutes
However, chemically synthesized peptides usually have a disordered structure, and it is difficult to maintain their secondary structure under physiological conditions.

Method used

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  • GLP-1 derivative and preparation method and application thereof
  • GLP-1 derivative and preparation method and application thereof
  • GLP-1 derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Embodiment 1: the synthesis of GLP-1 derivative Ia

[0083] (1) Synthesis of Cys-substituted linear peptides

[0084] Weigh 1 g of Wang resin with a substitution degree of 0.6 mmol / g in a solid phase reactor, add DCM to swell for 20 min, then add 20% PIP / DMF solution to react for 20 min to remove the Fmoc protecting group, wash with DCM, MeOH and DMF respectively Time, drain. Add Fmoc-Gly-OH (0.36g, 1.2mmol), HOBt (0.19g, 1.44mmol), DIC (0.23mL, 1.44mmol), DMF (5mL) into the solid phase reactor, and react at 25°C for 1h. The resin was washed and dried to obtain Fmoc-Gly-Wang resin, and the measured resin substitution degree was 0.5 mmol / g. Add 4 mL of blocking reagent (acetic anhydride (mmol): DIPEA (mmol) = 1:1) to the resin, react for 2.5 h, block the remaining amino groups, and use DCM (1 time), MeOH (1 time) and DMF (3 times) washing. Add 20% PIP / DMF solution and react for 20 minutes to remove the Fmoc protecting group, wash with DCM (once), MeOH (once) and DMF ...

Embodiment 2

[0089] Example 2: Synthesis of GLP-1 derivative IIIb

[0090] (1) Synthesis of Cys-substituted linear peptides

[0091] With step (1) of embodiment 1, the only difference is that the Cys replacement position and amino acid are Asp 15 and Gly 22 .

[0092] (2) Synthesis of GLP-1 derivative IIIb

[0093] Weigh 0.1 g of the Cys-substituted linear polypeptide obtained in step (1), place it in a 50 mL round bottom flask, add 8 mL of acetonitrile aqueous solution (acetonitrile: water = 2: 1) to dissolve, and adjust the pH to 8 with saturated ammonium bicarbonate solution -9; 150 mg of 4,4'-bis(bromomethyl)diphenylamine dissolved in 3 mL of acetonitrile was added into a round-bottomed flask, stirred for 1 h, and 0.3 mL of acetic acid was added to quench the reaction, and the obtained product was separated and purified by HPLC. Freeze-dry to obtain GLP-1 derivative IIIb.

Embodiment 3

[0094] Example 3: Synthesis of GLP-1 derivative IXc

[0095] (1) Synthesis of Cys-substituted linear peptides

[0096] With embodiment 1 step (1), the only difference is that the Cys replacement position and amino acid are Ala 24 and Trp 31 .

[0097] (2) Synthesis of GLP-1 derivative IXc

[0098] Weigh 0.1 g of the Cys-substituted linear polypeptide obtained in step (1), place it in a 50 mL round bottom flask, add 8 mL of acetonitrile aqueous solution (acetonitrile: water = 2: 1) to dissolve, and adjust the pH to 8 with saturated ammonium bicarbonate solution -9; Add 120 mg of N,N'-(oxybis(4,1-phenylene))bis-(2-bromoacetamide) dissolved in 3 mL of acetonitrile into a round bottom flask, stir for 0.5 h, add 0.3 mL of acetic acid to quench reaction, the obtained product was separated and purified by HPLC, and freeze-dried to obtain the GLP-1 derivative IXc.

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Abstract

The invention discloses a GLP-1 derivative, and further discloses a preparation method and an application of the GLP-1 derivative. The derivative is a compound obtained by replacing amino acids on the ith and the (i+7)th positions of a sequence GLP-1 (7-37) with Cys, wherein the value of i is 13, 14, 15, 16, 17, 18, 20, 23, 24 or 27; and forming a ring through a connecting arm. The GLP-1 derivative prepared by the method has in vivo blood glucose reduction time which is longer than that of natural GLP-1, and is especially suitable for being used as an active component of the medicine in preparation of the medicine for treating diabetes.

Description

technical field [0001] The invention relates to the field of therapeutic polypeptides, in particular to novel long-acting GLP-1 derivatives and a preparation method thereof, and also to the medical use of these derivatives. Background technique [0002] Glucagon-Like Peptide 1 (GLP-1) is a peptide hormone encoded by the human glucagon gene and secreted by intestinal L cells. It has the following important physiological functions: Act on pancreatic β cells in a glucose-dependent manner, promote the transcription of insulin gene, increase the biosynthesis and secretion of insulin; stimulate the proliferation and differentiation of β cells, inhibit the apoptosis of β cells, thereby increasing the number of pancreatic β cells and inhibiting glucagon secretion, inhibit appetite and food intake, delay the emptying of gastric contents, etc. These functions are beneficial to reduce postprandial blood sugar and maintain blood sugar at a constant level. [0003] GLP-1 can be used in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10
CPCC07K14/605A61K38/00
Inventor 苏贤斌杨敏敏李金科郭伦迪汤同洋
Owner NANJING UNIV OF TECH
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