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A kind of cyclic antimicrobial peptide analogue rich in positive charge and its application

A technology of antimicrobial peptides and analogs, applied in the field of biochemistry, can solve the problems of strong side effects and bacterial drug resistance, and achieve the effects of strong antibacterial activity, not easy to induce bacterial drug resistance, and high metabolic stability

Active Publication Date: 2022-04-22
JIANGXI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, polymyxin B has strong nephrotoxic side effects and long-term use will produce bacterial resistance, so its clinical use is strictly restricted

Method used

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  • A kind of cyclic antimicrobial peptide analogue rich in positive charge and its application
  • A kind of cyclic antimicrobial peptide analogue rich in positive charge and its application
  • A kind of cyclic antimicrobial peptide analogue rich in positive charge and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] This example provides a positively charged cyclic antimicrobial peptide analogue, which is based on a derivative of the natural antimicrobial peptide gramicidin tyrosin A skeleton, which is obtained by introducing amino acids into its skeleton. Its structure The general formula is: cyclo-( D FPF D FXXXZXZ), wherein F=Phe, P=Pro, X=Gln, Orn, Lys, Arg, Tyr or Asn, Z=Val, Leu, Orn, Lys or Arg, and the left superscript D represents a D-type amino acid.

[0062] The structural formula of the cyclic antimicrobial peptide analog is as follows:

[0063] cycle -( D FPF D FNOOVOL), labeled as compound 1;

[0064] cycle -( D FPF D FOOYVOL), labeled as compound 2;

[0065] cycle -( D FPF D FOQOVOL), labeled as compound 3;

[0066] cycle -( D FPF D FOOOVOL), labeled as compound 4;

[0067] cyclo- ( D FPF D FOOOOOL), labeled as compound 5;

[0068] cycle -( D FPF D FOOOVOO), labeled as compound 6;

[0069] cycle -( D FPF D FOOOOOO), labeled as compound 7;...

Embodiment 2

[0086] This embodiment provides the synthesis method of compound 3, and the specific steps are:

[0087] (1) Swelling of the resin

[0088] Put 210mg of Fmoc-Pro-2-CTC resin (substitution value 0.476 mmol / g) in the peptide synthesis tube, and swell with DCM solution for 15 minutes;

[0089] (2) Synthesis of linear peptides

[0090] For the above-mentioned swollen Fmoc-Pro-2-CTC resin, the DMF solution containing 20% ​​piperidine by volume was shaken twice for 15 minutes each time to remove the Fmoc protecting group; then washed twice with DMF and twice with MeOH, DCM washed 2 times, DMF washed 1 time, Fmoc- D Phe-OH (194 mg), HOBT (67.6 mg), HBTU (189 mg), and DIEA (0.25 mL) were dissolved and mixed in 5 mL of DMF, and mixed with the above-mentioned Fmoc-Pro-2-CTC resin deprotected from Fmoc Mix, shake and condense for 1 h to obtain Fmoc- D Phe-Pro-2-CTC; then washed again with DMF for 2 times, MeOH for 2 times, DCM for 2 times, and DMF for 1 time. The method is the same ...

Embodiment 3

[0102] This example provides the synthesis method of compound 4, the difference from Example 2 is that the synthesis steps of the linear polypeptide are:

[0103] For the above swollen Fmoc-Pro-2 CTC, oscillate twice with a DMF solution containing 20% ​​piperidine by volume fraction, each time for 15 minutes, to remove the Fmoc protecting group; then wash twice with DMF, twice with MeOH, and then with DCM 2 times, washed 1 time with DMF, Fmoc- D Phe-OH (194 mg), HOBT (67.6 mg), HBTU (189 mg), and DIEA (0.25 mL) were dissolved in 5 mL DMF and mixed evenly, and mixed with the above-mentioned Fmoc-Pro-2 CTC resin that had removed the Fmoc protecting group Mix, shake and condense for 1 h to obtain Fmoc- D Phe-Pro-2 CTC; then washed again with DMF 2 times, MeOH 2 times, DCM 2 times, DMF 1 time. The method is the same as above, followed by condensation reaction of amino acids: Fmoc-Leu-OH (177 mg), Fmoc-Orn(Boc)-OH (227 mg), Fmoc-Val-OH (170mg), Fmoc-Orn(Boc)-OH ( 227 mg), Fmoc-O...

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Abstract

The invention discloses a positively charged cyclic antimicrobial peptide analogue, which is a derivative based on the skeleton of the natural antibacterial peptide gramicidin tyrosin A, which is obtained by introducing amino acids into the skeleton, and its structure is generally The formula is: cyclo‑( D FPF D FXXXZXZ), the present invention also discloses the synthesis method of the cyclic antimicrobial peptide analog and its application in the preparation of clinical antibacterial drugs. The invention has the advantages of simple design, low production cost, high metabolic stability, strong antibacterial activity, low hemolytic toxicity and difficult induction of bacterial drug resistance.

Description

technical field [0001] The invention belongs to the technical field of biochemistry, and more specifically relates to a positive-charge-rich cyclic antimicrobial peptide analog and application thereof. Background technique [0002] According to the statistics of the World Health Organization, millions of people around the world are infected with drug-resistant Staphylococcus aureus (MRSA) every year, and about 30% of them will die. Due to the inappropriate and excessive use of antibiotics, a large number of multi- and extensively resistant bacteria and even superbugs have emerged. The increasing bacterial resistance is a severe reality that every citizen must face. [0003] In the process of researchers actively seeking new antibacterial drugs, antimicrobial peptides have attracted much attention because of their unique mechanism of action, broad antibacterial spectrum, and resistance to drug resistance. There are many kinds of antimicrobial peptides, but their structures a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/66C07K1/08C07K1/06C07K1/04C07K1/20A61K38/12A61P31/04
CPCC07K7/66A61P31/04A61K38/00Y02P20/55
Inventor 万阳祝及宝胡成飞曾子珍金一
Owner JIANGXI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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