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Method for synthesizing tetrapeptide isomers by using solid phase peptide synthesis method and applications of tetrapeptide isomers

A technology for solid-phase peptide synthesis and isomerization, applied in peptide preparation methods, tetrapeptide components, chemical instruments and methods, etc., can solve problems such as concentration drop and limitation of biological activity

Active Publication Date: 2012-07-11
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0005] Ac-S-D-K-P has very significant anti-fibrosis and anti-inflammatory characteristics, but because it enters the human body, it is rapidly degraded under the action of ACE in the body, and its concentration is greatly reduced, which greatly limits its biological activity.
Therefore, it is of great significance to provide an Ac-S-D-K-P short peptide with a stable structure, which can resist the degradation of ACE in the body and exert its biological function for a long time, but so far, there have been no relevant research reports at home and abroad.

Method used

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  • Method for synthesizing tetrapeptide isomers by using solid phase peptide synthesis method and applications of tetrapeptide isomers
  • Method for synthesizing tetrapeptide isomers by using solid phase peptide synthesis method and applications of tetrapeptide isomers
  • Method for synthesizing tetrapeptide isomers by using solid phase peptide synthesis method and applications of tetrapeptide isomers

Examples

Experimental program
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Effect test

Embodiment 1

[0080] The synthetic method of embodiment 1 tetrapeptide isomers

[0081] The synthesis process of tetrapeptide isomer ① (N-Acetyl-Ser-(d)Asp-Lys-Pro-COOH) starting from 5g of dichloro resin as an example:

[0082] 1. Synthesis of Peptide Resin

[0083] (1) Preparation of Fmoc-Pro-resin:

[0084] Weigh 5 grams of 2-chloro-tritylchloromethyl resin, soak it with 100ml of dichloromethane (DCM) for 60 minutes, add 4.5ml of DIEA, 3.38g of Fmoc-Pro-OH to the above resin, and react at 25°C for 2 hour, then add blocking reagent methanol 1.5ml, react for 2 hours at 25°C, wash the resin twice with 35ml isopropanol, and then wash twice with 35ml N,N-dimethylformamide (DMF) to obtain Fmoc-Pro- resin;

[0085] (2) Preparation of Fmoc-Lys(Boc)-OH resin:

[0086] In the Fmoc-Pro-resin of step (1), add 35ml of decapping reagent, react at 25°C for 10 minutes, dry it with a vacuum pump, add 35ml of decapping reagent at 25°C for 30 minutes, dry it, wash with 35ml of isopropanol for 2 Wash t...

Embodiment 2

[0105] The synthetic method of embodiment 2 tetrapeptide isomers (unblocked)

[0106] The synthetic process of tetrapeptide isomer ① (N-Acetyl-Ser-(d)-Asp-Lys-Pro-COOH) starting from 5g of dichloro resin as an example:

[0107] Compared with Example 1, the difference of this example is that no blocking reagent is added in Step 1, and the step of preparing Fmoc-Pro-resin in Step 1 is specifically:

[0108] Weigh 5 grams of 2-chloro-tritylchloromethyl resin, soak it with 100ml of dichloromethane (DCM) for 60 minutes, add 4.5ml of DIEA, 3.38g of Fmoc-Pro-OH to the above resin, and react at 25°C for 2 Hour, resin washes twice with 35ml isopropanol, then washes twice with 35ml N, N-dimethylformamide (DMF), obtains Fmoc-Pro-resin;

[0109] In this example, N-Acetyl-Ser-(d)Asp-Lys-Pro was synthesized by an unblocked method, the purity of the crude product was 84.8936%, and the purity of the pure product was 98% (HPLC normalization method). The rate is 61.7%. Crude product chromato...

Embodiment 3

[0110] Embodiment 3 The synthetic method of tetrapeptide isomer 2.

[0111] The synthesis process of tetrapeptide isomer ② (N-Acetyl-Ser-Asp-d-Lys-Pro-COOH) starting from 5g of dichloro resin as an example:

[0112] 1. Synthesis of Peptide Resin

[0113] (1) Preparation of Fmoc-Pro-resin:

[0114] Weigh 5 grams of 2-chloro-tritylchloromethyl resin, soak it with 100ml of dichloromethane (DCM) for 60 minutes, add 4.5ml of DIEA, 3.38g of Fmoc-Pro-OH to the above resin, and react at 25°C for 2 hour, then add blocking reagent methanol 1.5ml, react for 2 hours at 25°C, wash the resin twice with 35ml isopropanol, and then wash twice with 35ml N,N-dimethylformamide (DMF) to obtain Fmoc-Pro- resin;

[0115] (2) Preparation of Fmoc-D-Lys(Boc)-OH resin:

[0116] In the Fmoc-Pro-resin of step (1), add 35ml of decapping reagent, react at 25°C for 10 minutes, dry it with a vacuum pump, add 35ml of decapping reagent at 25°C for 30 minutes, dry it, wash with 35ml of isopropanol for 2 Was...

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Abstract

The invention discloses a method for synthesizing tetrapeptide isomers by using solid phase peptide. The method includes using any of trityl chloride-type resins as a starting raw material, sequentially linking fmoc-protected amino acids according to the solid phase synthesis method, obtaining tetrapeptide isomer resins, meanwhile sequentially removing fmoc protecting groups, using a condensing agent to perform a peptide synthesis reaction, simultaneously removing side chain protecting groups and cutting peptides after obtaining protected tetrapeptide isomer resins, obtaining crude tetrapeptide isomers, separating and purifying the crude tetrapeptide isomers through C18 or C8 chromatographic column, and then obtaining the tetrapeptide isomers. According to the protected tetrapeptide isomer synthesis method required by the method for synthesizing the tetrapeptide isomers, raw and auxiliary materials are convenient to collect, the process is stable, the production cycle is short, the production cost is low, the yield is high, the purity is fine, the quality is stable, large-scale production can be achieved, and the market competition ability is high.

Description

technical field [0001] The present invention relates to a preparation method of tetrapeptide isomers, specifically, the present invention relates to a method for synthesizing tetraisomers by solid-phase polypeptide synthesis method and its application. Background technique [0002] N-acetyl-serine-aspartic acid-lysine-proline (N-Acetyl-Ser-Asp-Lys-Pro), abbreviated as Ac-S-D-K-P, is an endogenous N-terminal acetylated Tetrapeptides are widely distributed in various tissues and body fluids in the body. This tetrapeptide is released primarily from its precursor thymosin β4 via prolyl oligopeptidase (POP) hydrolysis. The concentration in blood is generally nanomolar. The pharmacokinetic study of Ac-S-D-K-P found that Ac-S-D-K-P was degraded soon after intravenous injection into the body, with a half-life of only 4 to 5 minutes. Ac-S-D-K-P is cleared from plasma through two mechanisms in the human body: ① angiotensin-converting enzyme (ACE)-mediated hydrolysis; ② glomerular f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/103C07K1/06C07K1/04A61K9/19A61K38/07A61P1/16A61P9/00A61P11/00A61P13/12A61P29/00
CPCY02P20/55
Inventor 张英起王增禄张昭杨赛李萌张伟黄同列
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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