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Antimicrobial peptide analogs containing d-type unnatural amino acids and their synthesis and application

A technology of unnatural amino acids and antimicrobial peptides, which is applied in the field of biochemistry and can solve problems such as poor enzymatic hydrolysis stability, destruction of mammalian cells, and restriction of the development of natural antimicrobial peptides.

Active Publication Date: 2020-06-30
倪京满
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, natural antimicrobial peptides also have some disadvantages, such as poor enzymatic stability and low bioavailability; poor selectivity and destructive effects on mammalian cells, etc., which will limit the further development of natural antimicrobial peptides

Method used

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  • Antimicrobial peptide analogs containing d-type unnatural amino acids and their synthesis and application
  • Antimicrobial peptide analogs containing d-type unnatural amino acids and their synthesis and application
  • Antimicrobial peptide analogs containing d-type unnatural amino acids and their synthesis and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1, the synthesis of analogue Anoplin-D9,10

[0046] Weigh Rink-MBHA resin, the substitution value is 0.43mmol / g, the amount of peptide synthesis is 0.15mmol, add redistilled dichloromethane solution, fully stir and swell the resin for 30min, then add 10% hexahydropyridine to remove the resin Fmoc protection, wash 2 minutes each time, wash 4 times in total, then wash the resin with redistilled DMF solution, wash the resin 2 minutes each time, wash 4 times in total, and finally use indene detection indicator (phenol: potassium cyanide pyridine: ninhydrin = 1:2:1) Check whether the Fmoc protecting group has been removed from the resin, boil the resin for 1 min, observe immediately, and the resin turns blue, which proves that the Fmoc group has been removed. According to the sequence of the peptide, start from the C-terminus and weigh The first amino acid is d-Leu, 1.5-fold excess, add HOBT (1-fold excess), HBTU (1-fold excess), after the amino acid is dissolved,...

Embodiment 2

[0047] Example 2 Synthesis of Analog Anoplin-D9,10,3

[0048] Weigh Rink-MBHA resin, the substitution value is 0.43mmol / g, the amount of peptide synthesis is 0.25mmol, add redistilled dichloromethane solution, fully stir and swell the resin for 30min, then add 15% hexahydropyridine to remove the resin Fmoc protection, wash 2 minutes each time, wash 4 times in total, then wash the resin with redistilled DMF solution, the same 2 minutes each time, wash 4 times in total, and then detect the indicator (phenol: potassium cyanide pyridine: ninhydrin = 1 :2:1) test, the resin turns blue, which proves that the Fmoc group on the resin has been removed. According to the sequence of the peptide, starting from the C-terminus, weigh the first amino acid d-Leu amino acid, and add HOBT to a 2-fold excess (3 times excess), HBTU (3 times excess), after the amino acid is dissolved, add starter DIEA (6 times excess). The above amino acid and the resin were stirred and reacted together for 1.5 h...

Embodiment 3

[0049] Embodiment 3, the synthesis of analogue Anoplin-D4,7

[0050] Weigh the Rink-MBHA resin, the substitution value is 0.43mmol / g, the amount of peptide synthesis is 0.2mmol, add redistilled dichloromethane solution, fully stir and swell the resin for 30min, then add 15% hexahydropyridine to remove the resin Fmoc protection, wash 2 minutes each time, wash 4 times in total, then wash the resin with redistilled DMF solution, the same 2 minutes each time, wash 4 times in total, and then detect the indicator (phenol: potassium cyanide pyridine: ninhydrin = 1 :2:1) test, the resin turns blue, which proves that the Fmoc group has been released. According to the sequence of the peptide, starting from the C-terminus, weigh the first amino acid Leu, 3-fold excess, add HOBT (5-fold excess), HBTU (5-fold excess), after the amino acid is dissolved, add starter DIEA (6-fold excess). Stir and react the above amino acid with the resin for 1 hour. After the reaction, check with ninhydrin....

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Abstract

The invention discloses a D-type amino acid containing antimicrobial peptide analog. The D-type amino acid containing antimicrobial peptide analog is obtained through separately introducing D-type amino acids to a hydrophilic surface and a hydrophobic surface of a natural antimicrobial peptide Anoplin and modifying the hydrophilic surface and the hydrophobic surface. Shown by determination on minimal inhibitory concentration to common standard bacteria, biomembrane formation inhibiting tests and enzymolysis stability tests, synthesized hydrophilic-surface D-type peptide analogs all reserve the antimicrobial activity of the original stock peptide and meanwhile represent relatively high bacterial biomembrane formation inhibiting capability. The chymotrypsin tolerance is enhanced by 10 times compared with that of the stock peptide Anoplin. Although the antimicrobial activity of synthesized hydrophobic-surface D-type substituted analogs is lowered to some extent compared with that of the stock peptide, the stability of the synthesized hydrophobic-surface D-type substituted analogs is improved remarkably; and compared with the stock peptide, the trypsin tolerance is improved by 10<4> to 10<5> times, and the chymotrypsin tolerance is improved by 10<2> times. Therefore, the synthesized D-type amino acid containing analog has a very good application prospect in the aspect of preparation of long-acting clinical antibacterials.

Description

technical field [0001] The present invention relates to a D-type non-natural antimicrobial peptide analog with good stability against enzymolysis. The present invention also relates to the success and success of the D-type non-natural antibacterial peptide analog and its application in the preparation of antibacterial drugs. The application belongs to the technical field of biochemistry. Background technique [0002] In recent years, the problem of drug resistance caused by the abuse of antibiotics has become increasingly serious, posing a huge threat to human diseases. It is imminent to find new drugs that can replace antibiotics. Antimicrobial peptides are a class of small molecular peptides with antibacterial activity induced by organisms. They come from a wide range of sources, and their molecular weight is small, about 3-6 kD. They are heat-resistant, acid-resistant, and water-soluble. Well, rapid bactericidal ability and other characteristics (Hancock REW, Scott MG. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06A61K38/08A61P31/04
CPCA61K38/00C07K7/06
Inventor 倪京满刘倍均王一杰王锐
Owner 倪京满
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