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基于流的 Fmoc-SPPS 制备和 Cathelicidin-PY 的 SAR 研究揭示了选择性抗菌活性。

Flow-Based Fmoc-SPPS Preparation and SAR Study of Cathelicidin-PY Reveals Selective Antimicrobial Activity.

机构信息

School of Chemical Sciences and School of Biological Sciences, The University of Auckland, 23 Symonds St., Auckland 1142, New Zealand.

Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1142, New Zealand.

出版信息

Molecules. 2023 Feb 20;28(4):1993. doi: 10.3390/molecules28041993.

DOI:10.3390/molecules28041993
PMID:36838983
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9959817/
Abstract

Antimicrobial peptides (AMPs) hold promise as novel therapeutics in the fight against multi-drug-resistant pathogens. Cathelicidin-PY (NH-RKCNFLCKLKEKLRTVITSHIDKVLRPQG-COOH) is a 29-residue disulfide-cyclised antimicrobial peptide secreted as an innate host defence mechanism by the frog (PY) and reported to possess broad-spectrum antibacterial and antifungal properties, exhibiting low cytotoxic and low hemolytic activity. Herein, we detail the total synthesis of cathelicidin-PY using an entirely on-resin synthesis, including assembly of the linear sequence by rapid flow Fmoc-SPPS and iodine-mediated disulfide bridge formation. By optimising a synthetic strategy to prepare cathelicidin-PY, this strategy was subsequently adapted to prepare a bicyclic head-to-tail cyclised derivative of cathelicidin-PY. The structure-activity relationship (SAR) of cathelicidin-PY with respect to the -terminally positioned disulfide was further probed by preparing an alanine-substituted linear analogue and a series of lactam-bridged peptidomimetics implementing side chain to side chain cyclisation. The analogues were investigated for antimicrobial activity, secondary structure by circular dichroism (CD), and stability in human serum. Surprisingly, the disulfide bridge emerged as non-essential to antimicrobial activity and secondary structure but was amenable to synthetic modification. Furthermore, the synthetic AMP and multiple analogues demonstrated selective activity towards Gram-negative pathogen in physiologically relevant concentrations of divalent cations.

摘要

抗菌肽 (AMPs) 作为一种新型治疗方法，有望对抗多种耐药病原体。Cathelicidin-PY (NH-RKCNFLCKLKEKLRTVITSHIDKVLRPQG-COOH) 是一种 29 个残基的二硫键环化抗菌肽，作为先天宿主防御机制由青蛙分泌，具有广谱抗菌和抗真菌特性，表现出低细胞毒性和低溶血活性。在此，我们详细介绍了使用完全在树脂上合成 Cathelicidin-PY 的全合成，包括通过快速流动 Fmoc-SPPS 组装线性序列和碘介导的二硫键形成。通过优化合成策略来制备 Cathelicidin-PY，随后将该策略改编为制备 Cathelicidin-PY 的双环头尾环化衍生物。通过制备丙氨酸取代的线性类似物和一系列酰胺桥接的肽模拟物，进一步研究了 Cathelicidin-PY 相对于 -末端二硫键的结构-活性关系 (SAR)，实现侧链到侧链环化。研究了类似物的抗菌活性、圆二色性 (CD) 测定的二级结构以及在人血清中的稳定性。令人惊讶的是，二硫键对抗菌活性和二级结构不是必需的，但可进行合成修饰。此外，合成的 AMP 和多种类似物在生理相关浓度的二价阳离子下对革兰氏阴性病原体表现出选择性活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51a9/9959817/71dce7e97ee2/molecules-28-01993-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51a9/9959817/3e588e674f10/molecules-28-01993-sch002.jpg
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