Antibacterial polypeptide conjugate with multiple target points and synthesis method and application of biopolymer of antibacterial polypeptide conjugate

A technology of antibacterial polypeptides and peptide conjugates, applied in the preparation of antibacterial drugs, in the field of antibacterial polypeptide conjugates, can solve the problems of drug resistance and other problems

Active Publication Date: 2015-10-07
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Antibiotics discovered so far basically inhibit and kill bacteria through a single mechanism of action, which can easily lead to bacterial resistance to such drugs

Method used

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  • Antibacterial polypeptide conjugate with multiple target points and synthesis method and application of biopolymer of antibacterial polypeptide conjugate
  • Antibacterial polypeptide conjugate with multiple target points and synthesis method and application of biopolymer of antibacterial polypeptide conjugate
  • Antibacterial polypeptide conjugate with multiple target points and synthesis method and application of biopolymer of antibacterial polypeptide conjugate

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Experimental program
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Effect test

Embodiment 1

[0067] Embodiment 1, antimicrobial polypeptide conjugate Acr with multiple targets 3 - Synthesis of NLS

[0068] (1) Synthesis of amino acid Fmoc-Lys(Acr) containing acridine group

[0069] a. Synthesis of 9-phenoxyacrudine: Weigh 150mmol phenol, 22.5mmol NaOH, and 15mmol 9-chloroacridine respectively, add them to a 100mL round-bottomed flask, add a magnet of suitable size, seal the flask mouth with a rubber stopper and a rubber band, The system was evacuated and filled with argon protection. Heating in an oil bath, the temperature is controlled at about 100°C (reaction requires reflux of condensed water). After 2 hours of reaction, add 100mL of 2M NaOH solution to the flask to terminate the reaction. After standing overnight at room temperature, a yellow precipitate appeared. Filter, wash with water 3-4 times, and drain to obtain relatively pure product 9-phenoxyacrudine with a yield of 96.3%. The reaction formula is as follows:

[0070]

[0071] b. Synthesis of Fmoc-...

Embodiment 2

[0081] Embodiment 2, antibacterial polypeptide dimer (Acr 3 -NLS) 2 Synthesis

[0082] (1) Antimicrobial peptide Acr 3 -Activation of cysteine ​​side chain sulfhydryl group in NLS sequence: 0.4 mmol dithiobipyridine was dissolved in 2 mL methanol solution; 0.04 mmol Acr 3 -NLS was dissolved in 1mL methanol / water (V / V=1:1~1:10), and added dropwise to the methanol solution of dithiobipyridine above, and reacted for 10~16 h, using a C18 reversed HPLC column Purified by chromatography to obtain sulfhydryl-activated Acr 3 -NLS;

[0083] (2) dimer (Acr 3 -NLS) 2 Synthesis of: 0.01 mmol thiol-activated Acr 3 -NLS with 0.015 mmol unactivated Acr 3 -NLS was dissolved in 2 mL of methanol / water (V / V=1:1~1:10), reacted for 10~16 h, and purified by HPLC to obtain the dimer (Acr 3 -NLS) 2 , and the yield was 37.5%.

[0084] The product prepared by the above method was detected by mass spectrometry and chromatographic analysis, and was consistent with the designed compound structu...

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Abstract

The invention provides an antibacterial polypeptide conjugate Acr3-NLS (nuclear localization sequence) as well as a bipolymer (Acr3-NLS)2 of the antibacterial polypeptide conjugate, and belongs to the field of medicinal chemistry. The antibacterial polypeptide conjugate Acr3-NLS is formed by connecting acridine molecules to an N end of NLS, and the biopolymer (Acr3-NLS)2 is formed by connecting Acr3-NLS molecules by virtue of a disulfide bond. The activity test shows that the antibacterial activity of the antibacterial polypeptide conjugate Acr3-NLS and (Acr3-NLS)2 is remarkably improved compared with that of the NLS, and the bacteria can be killed by virtue of the action mechanism of multiple target points. The action mechanism of the multiple target points can enable the Acr3-NLS and (Acr3-NLS)2 to kill the traditional antibiotics drug-fastness bacteria; moreover, the bacteria is unlikely to have drug fastness. The Acr3-NLS and (Acr3-NLS)2 as an active ingredient have a potential application value in preparing the antibacterial drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a multi-target antibacterial polypeptide conjugate; the invention also relates to the application of the antibacterial peptide in preparing antibacterial drugs. Background technique [0002] In the long river of human development, bacterial infection has claimed the lives of countless people. Since the advent of penicillin, a large number of antibacterial drugs have been emerging, which have played a great role in the treatment of bacterial infection diseases. However, due to the irrational application of antibacterial drugs, bacterial drug resistance occurs frequently, and even the speed of drug resistance tendency far exceeds the speed of antibacterial drug research and development. Antimicrobial resistance has become a serious public health problem worldwide. In particular, the emergence of "super bacteria" has made human beings face the dilemma that no medicine is available....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04C07K19/00A61K47/48A61K31/473A61P31/04
Inventor 王锐宋竟婧张伟张邦治
Owner LANZHOU UNIVERSITY
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