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A kind of polypeptide compound with high affinity to glp-1 receptor and its preparation method and application

A technology for GLP-1 and peptide compounds, which is applied in the fields of pharmaceutical preparations and biomedicine, can solve the problems of limited clinical application, cannot meet the needs of long-term storage and transportation of medicines, etc., and achieves a simple and easy preparation method, easy storage, and obvious curative effect. Effect

Active Publication Date: 2019-03-01
SHANGHAI THERANOSTICS BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have found that the stability of such peptides needs to be improved, which cannot meet the needs of long-term storage and transportation of drugs, resulting in limited clinical applications.

Method used

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  • A kind of polypeptide compound with high affinity to glp-1 receptor and its preparation method and application
  • A kind of polypeptide compound with high affinity to glp-1 receptor and its preparation method and application
  • A kind of polypeptide compound with high affinity to glp-1 receptor and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 1) Preparation of maleimide Evans blue derivatives:

[0048] a. Preparation of intermediate maleyl xylidine Mal-tolidine

[0049] 3-Maleimidopropionic acid (10.0mmol), HATU (20mmol) and DIPEA (50.0mmol) were successively cast into acetonitrile (500mL) solution of 3,3'-dimethylbenzidine tolidine (50.0mmol) . After stirring at room temperature for 48 h, the reaction mixture was filtered, and the filtrate was spin-dried to remove the solvent to obtain a yellow crude product. The residue was purified by a silica gel column to obtain a pale yellow intermediate Mal-C3-Tolidine, whose characterization is shown in figure 1 , 2 , yield 60%. The reaction process is as follows:

[0050]

[0051] b. Preparation of Evans blue (MEB) with maleimide groups

[0052] Dissolve Mal-tolidine (5.0 mmol) prepared in step a into a mixed solvent of acetonitrile and water to obtain a yellow solution. Under the condition of ice bath, HCl was slowly added dropwise to the above Mal-tolidi...

Embodiment 2

[0069] Add 5mL [Leu] to the sodium acetate solution (50mM, pH 5.5) of Evans blue (1mmol) with aldehyde group 14 Exendin-4 (1mmol) was dissolved in 50mM sodium acetate solution (50mM, pH 5.5), and then 20mM NaCNBH was added 3 reducing agent. Under the condition of avoiding light, react at room temperature for 2 hours. Terminate the reaction with 0.1% aqueous trifluoroacetic acid (TFA), react the mixture, lyophilize the reaction mixture to obtain a lyophilized mixture, then dissolve the lyophilized mixture in PBS buffer with a pH of 7.0, and remove unreacted by dialysis substance, and finally Evan's blue-modified [Leu] 14 Exendin-4.

Embodiment 3

[0071] Add 5mL of [Leu] 14 Exendin-4 (1mmol) was dissolved in 50mM sodium acetate solution (50mM, pH 5.5), and then 20mM NaCNBH was added 3 reducing agent. Under the condition of avoiding light, react at room temperature for 2 hours. Terminate the reaction with 0.1% aqueous trifluoroacetic acid (TFA), react the mixture, freeze-dry the reaction mixture to obtain a freeze-dried mixture, then dissolve the freeze-dried mixture in PBS buffer with a pH of 8.5, and remove the unreacted mixture by dialysis substance, and eventually Evan's blue modified [Leu] 14 Exendin-4.

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Abstract

The present invention provides a polypeptide compound having high affinity for GLP-1 receptors, the molecular structure thereof being as shown in the following formula (I), wherein R represents Evans blue or a derivative group thereof. The polypeptide compound of the present invention has the advantages of stable structure, simple preparation, significant therapeutic effect, long-term drug efficacy, convenient storage, etc. The present invention further provides a preparation method for the polypeptide compound and use thereof in preparing a medicament for diagnosing, preventing or treating GLP-1 / GLP-1 receptor pathway-related diseases.

Description

technical field [0001] The invention belongs to the field of biomedicine and pharmaceutical preparations, and in particular relates to a polypeptide compound with high affinity for GLP-1 receptors, a preparation method thereof and its use in the preparation of GLP-1 or GLP-1 receptor pathway-related diseases Applications in diagnostic, prophylactic or therapeutic medicine. Background technique [0002] The main function of glucagon peptide-1 (GLP-1) is to stimulate insulin secretion, inhibit glucagon secretion, promote satiety, inhibit gastrointestinal motility, increase glucose uptake and reduce body weight. In non-insulin-dependent diabetes mellitus (NIDDM), GLP-1 can promote the growth of new cells and restore insulin secretion without lowering blood sugar. In addition, GLP-1 does not cause any toxic side effects through the route of injection. Therefore, GLP-1 plays an important role in the treatment of type II diabetes. In addition, GLP-1 receptors are expressed in b...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/575C07K1/107A61K38/22A61K47/54A61P3/10A61P9/10
CPCA61K38/00C07K14/57563
Inventor 陈小元刘熠郎立新
Owner SHANGHAI THERANOSTICS BIOTECH CO LTD
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