Side chain fatty acid modified antimicrobial peptide analogues containing D-type amino acid and synthesis and application thereof

A technology of amino acids and fatty acids, applied in the field of biochemistry, can solve problems such as high manufacturing cost, intolerance of physiological conditions, and limitation of clinical application of AMPs

Pending Publication Date: 2019-07-26
倪京满 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, although compared with traditional antibiotics, AMPs are expected to defeat "super bacteria", but as an ideal antibacterial drug, they suffer from poor antibacterial activity, toxicity of host cells, intolerance to physiological conditions, sensitivity to enzymatic degradation, and High manufacturing cost due to complex design limits the clinical application of AMPs
A large number of studies have shown that the introduction of D-amino acids can effectively avoid the degradation of proteases and improve the enzymatic stability of antimicrobial peptides (Sci Rep.2017Jul 31; 7(1):6953; Chem Biol Drug Des.2006Feb; 67(2 ):162-73), but the introduction of D-type amino acid usually leads to the decrease of its antibacterial activity

Method used

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  • Side chain fatty acid modified antimicrobial peptide analogues containing D-type amino acid and synthesis and application thereof
  • Side chain fatty acid modified antimicrobial peptide analogues containing D-type amino acid and synthesis and application thereof
  • Side chain fatty acid modified antimicrobial peptide analogues containing D-type amino acid and synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Ano-D4,7-4C 4 Synthesis

[0055] (1) Activation and pretreatment of resin

[0056] Accurately weigh 0.47g of MBHA resin (0.43mmol / g) and place it in a peptide solid-phase synthesizer. After the DCM solution swells for 30 minutes, the resin is colorless and transparent through the ninhydrin color test, indicating that the resin is normal.

[0057] (2) Synthesis of Fmoc-Ano-D4,7-4(Mtt)-resin

[0058] For the above-mentioned normal MBHA resin, the Fmoc protecting group was removed by the DMF solution containing 20% ​​piperidine by volume fraction, and the ninhydrin chromogenic method was used to detect that the resin was blue-purple, indicating that the protecting group had been removed; the Fmoc-Leu-OH (212mg), HOBT (81mg), HBTU (228mg), and DIEA (0.2mL) were dissolved in 5-10mL DMF and mixed evenly, added to the synthesizer and mixed with the above-mentioned MBHA resin from which the Fmoc protecting group was removed, and condensed for 1 hour; Triketone chr...

Embodiment 2

[0065] Example 2: Ano-D4,7-4C 8 Synthesis

[0066] (1) Activation and pretreatment of resin

[0067] With embodiment 1.

[0068] (2) Synthesis of Fmoc-Ano-D4,7-4(Mtt)-resin

[0069] With embodiment 1.

[0070] (3)Ano-D4,7-4C 8 Synthesis of -resin

[0071] The above-obtained Fmoc-Ano-D4,7-4(Mtt)-resin was removed with a DCM solution containing 1% TFA by volume to remove the side chain Mtt protecting group, and the ninhydrin colorimetric method showed that the resin was blue-purple. Indicates that the protecting group has been removed to obtain Ano-D4,7-4(NH 2 )-resin; Octanoic anhydride (C n , n=8; 1.53mL), HOBT (81mg), HBTU (228mg), DIEA (0.2mL) were dissolved and mixed in 5-10mL DMF, and added to the synthesizer with the above-mentioned Ano- D4,7-4(NH 2 )-resin mixed, condensation reaction 1.5h; ninhydrin color test, the resin was colorless and transparent, indicating that the condensation reaction was complete, and Ano-D4,7-4C was obtained 8 -resin; with the DMF so...

Embodiment 3

[0076] Example 3: Ano-D4,7-4C 12 Synthesis

[0077] (1) Activation and pretreatment of resin

[0078] With embodiment 1.

[0079] (2) Synthesis of Fmoc-Ano-D4,7-resin

[0080] With embodiment 1.

[0081] (3)Ano-D4,7-4C 12 Synthesis of -resin

[0082] The above-obtained Fmoc-Ano-D4,7-4(Mtt)-resin was removed with a DCM solution containing 1% TFA by volume to remove the side chain Mtt protecting group, and the ninhydrin colorimetric method showed that the resin was blue-purple. Indicates that the protecting group has been removed to obtain Ano-D4,7-4(NH 2 )-resin; Dodecanoic acid (C n , n=12; 240mg), HOBT (81mg), HBTU (228mg), DIEA (0.2mL) were dissolved and mixed in 5-10mL DMF, and added to the synthesizer with the above-mentioned Ano-D4 with the side chain Mtt protection group removed ,7-4(NH 2 )-resin mixed, condensation reaction 1.5h; ninhydrin color test, the resin was colorless and transparent, indicating that the condensation reaction was complete, and Ano-D4,7-4...

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Abstract

The invention designs and synthesizes side chain fatty acid modified antimicrobial peptide analogues containing D-type amino acid. A linear amphiphilic alpha-helical natural antibacterial peptide Anoplin is used as a template to replace the D-type amino acid to enhance the enzymatic stability and perform fatty acid modification on the replaced D-type amino acid side chain to enhance the activity of drug-resistant bacteria in the combination mode to obtain the side chain fatty acid modified antimicrobial peptide analogues containing the D-type amino acid with the brand new structure, includingAno-D4, 7-4Cn, Ano-D4 and 7-7Cn, n=4-16. In vitro bacteriostasis experiments, PI staining flow cytometry experiments and enzymatic stability experiments all show that the side chain fatty acid modified antimicrobial peptide analogues containing the D type amino acid have strong antibiotic resistance and high enzymatic stability. Compared with traditional antibiotics, the novel antimicrobial peptide analogues obtained have good application prospects in the development of clinical antibacterial drugs.

Description

technical field [0001] The present invention relates to the technical field of biochemistry, and relates to a new type of side chain fatty acid modified antimicrobial peptide analogue containing D-type amino acid and its synthesis and application, in particular to a type with strong anti-drug-resistant bacteria activity and high enzymatic stability Antimicrobial peptide analogs containing D-amino acid side chain fatty acid modification and their synthesis and application. Background technique [0002] In recent years, due to the abuse of traditional antibiotics in clinical medicine, drug-resistant strains, namely "super bacteria" have emerged continuously, and this "super bacteria" has shown resistance to most or all available antibiotics (HealthEcon.1996May -Jun;5(3):217-26). Polymyxin B and polymyxin E (also known as colistin), as cationic peptide antibacterial drugs, were widely used in the 1960s, but due to serious toxicity problems, their clinical application greatly d...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04A61K47/54A61K38/08A61P31/04
CPCC07K7/06A61K47/542A61K38/08A61P31/04Y02P20/55
Inventor 倪京满王锐钟超王一杰
Owner 倪京满
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