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Exendin-4 modified by Evans blue or derivatives of Evans blue and preparation method and application of Exendin-4

A technology of Evans blue and its derivatives, applied in the field of pharmaceutical preparations and biomedicine, can solve the problems of weakening the binding force between Exendin-4 and receptors, reducing the biological activity of Exendin-4, limiting the application of Exendin-4, etc., to achieve drug efficacy Long-lasting, easy to prepare, and easy to store effects

Active Publication Date: 2015-05-27
SHANGHAI THERANOSTICS BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since the lysine in the sequence needs to play a certain role when Exendin-4 binds to its receptor, when the Exendin-4 molecule is modified at a fixed point or randomly by this method, when the Exendin-4 molecule binds to its receptor, due to the existence of PEG, the Exendin The binding force between -4 and the receptor is weakened, thereby significantly reducing the biological activity of Exendin-4
In addition, using the random labeling method, the obtained product complex is greatly challenged in the separation and purification, which increases the cost of production and preparation
The above two points seriously limit the further clinical application of Exendin-4

Method used

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  • Exendin-4 modified by Evans blue or derivatives of Evans blue and preparation method and application of Exendin-4
  • Exendin-4 modified by Evans blue or derivatives of Evans blue and preparation method and application of Exendin-4
  • Exendin-4 modified by Evans blue or derivatives of Evans blue and preparation method and application of Exendin-4

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Experimental program
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Effect test

Embodiment 1

[0115] Preparation of Maleimide Evans Blue Derivatives

[0116] a.Boc-benzidine

[0117] Dissolve 4.3g of benzidine (dimethyl diaminobiphenyl) in 40ml of dichloromethane, place it in a 100ml round bottom flask, add 4.4g (4.6mL) of di-tert-butyl dicarbonate to the solution . Stir overnight at room temperature. Monitor the reaction process with thin-layer chromatography, climb the plate in the developer of n-hexane:ethyl acetate=7:3, three points (benzidine, Boc-benzidine, two-dicarbonic acid ditert-tert) appear butyl ester). After column separation, 3.2 g of the target product was obtained.

[0118] b.Boc-EB

[0119] 0.46 g of Boc-benzidine was dissolved in 10 ml of chloroform, and 15 ml of water (4.5 mmol of HCl in it) was added to the solution under ice cooling. Dissolve 0.31g NaNO2 in 5ml water under ice bath, and add this solution dropwise to the above solution, and stir for 20min under ice bath. At this point, the solution turned positive yellow indicating the forma...

Embodiment 2

[0136] Add 0.5mL Exendin-4 (1mg / mL in 50mM sodium acetate, pH 5.5) to Evans blue (0.76μmol in 50mM sodium acetate, pH 5.5) with aldehyde group, and then add 20mM NaC-NBH 3 as a reducing agent. The molar ratio of Evans blue to Exendin-4 is 1:1. Evan's blue and Exenatide-4 were reacted at 4°C for 2 hours under dark conditions. The reaction was terminated with 0.1% aqueous trifluoroacetic acid (TFA) to obtain Evans blue-modified Exendin-4.

Embodiment 3

[0138] Add 0.5 mL of Exendin-4 (1 mg / mL in PBS, pH 7.5) to Evans blue (0.76 μmol in PBS, pH 7.5) with a pyridyldithiol group, followed by 20 mM NaC -NBH 3 as a reducing agent. The molar ratio of Evans blue to Exendin-4 is 1:1. Evan's blue and Exenatide-4 were reacted at 4°C for 2 hours under dark conditions. The reaction was terminated with 0.1% aqueous trifluoroacetic acid (TFA) to obtain Evans blue-modified Exendin-4.

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Abstract

The invention relates to a preparation method and application of Exendin-4 biologically located and modified by Evans blue (Evans Blue) or derivatives of Evans blue. The product generated after the C terminal of Exendin-4 is specifically modified with Evans blue or derivatives of Evans blue has biological activity similar to Exendin-4 which is not modified but has longer in vivo half-life than the Exendin-4 which is not modified. Based on the significance of the Exendin-4 in treatment of diseases, the invention also discloses application of the Exendin-4 modified by Evans blue or derivatives of Evans blue in preparation of medicines for treating type-II diabetes and myocardial infarction. The Exendin-4 has the advantages of simplicity and convenience in preparation, obvious curative effect, long-lasting and stable drug effect, convenience in storage and the like and has significance in research and development of new drugs for promoting anti-diabetic and anti-infarction high-efficiency treatment.

Description

technical field [0001] The invention discloses a method for positionally modifying Exendin-4 by Evans Blue derivatives and the application of the positionally modified Exendin-4 in the treatment of type II diabetes and myocardial infarction, belonging to the fields of biomedicine and pharmaceutical preparations. Background technique [0002] The function of glucagon peptide-1 (hereinafter referred to as GLP-1) is mainly to induce various biological effects in the body, including stimulating insulin secretion, inhibiting glucagon secretion, promoting satiety, and inhibiting gastrointestinal Peristalsis, increased glucose uptake and weight loss. It has been reported that GLP-1 can effectively prevent pancreatic cell lesions caused by the development of type II diabetes. In non-insulin-dependent diabetes mellitus (NIDDM), GLP-1 can promote the growth of new cells and restore insulin secretion. GLP-1 has the remarkable property of promoting insulin secretion without lowering bl...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07K1/107A61K38/22A61K47/48A61P3/10A61P9/10A61K47/54
CPCA61K38/00A61K47/50C07K14/575
Inventor 陈小元朱雷郎立新
Owner SHANGHAI THERANOSTICS BIOTECH CO LTD
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