Stapled anoplin with perfluoroaryl-cysteine enhances antibacterial activity.

用全氟芳基半胱氨酸包被的阿诺普林可增强抗菌活性

Shiting Chen, Jiawei Chen, Xun Xu, Haobing Deng, Qi Peng, Ullah Shafi, Jiahao Chen, Anhui Mao, Yubo Long, Jinwu Zhao, Wenfang Xiong (2026) Stapled anoplin with perfluoroaryl-cysteine enhances antibacterial activity. Bioorg Chem (IF: 4.7) 2 区 176 109851

Abstract

Owing to their unique mechanism of action and broad-spectrum antimicrobial activity, antimicrobial peptides (AMPs) have gained considerable attention as promising antimicrobial alternatives. Anoplin is a natural antimicrobial peptide from the venom sac of the solitary wasp Anoplius samariensis featuring with broad-spectrum antibacterial activity, low hemolytic activity, and a low propensity to induce resistance. However, its relatively moderate potency and poor stability limited its further development and application. In this work, a peptide stapling strategy utilizing perfluoroaryl-cysteine or decafluorobiphenyl-cysteine was first applied to Anoplin, enabling the preparation of a series of conformationally constrained peptide analogues. The results indicated that these stapled peptides not only retained their antibacterial activity in the presence of physiological salt concentrations but also exhibited potent efficacy in serum, along with improved resistance to enzymatic degradation. In particular, Ano-(3-10) exhibited enhanced broad-spectrum antibacterial activity, low hemolytic toxicity, and efficacy under physiological salt and proteolytic conditions. Mechanistic studies indicated that these derivatives exert rapid antibacterial effects by disrupting outer bacterial membrane integrity, ultimately causing membrane collapse. Additionally, these analogs effectively inhibited biofilm formation. In a serial of passage experiments, E. coli and S. aureus failed to develop resistance to Ano-(3-10) over 15 passages. In summary, this study successfully developed a novel class of stapled antimicrobial peptide analogs with potent antimicrobial activity and high proteolytic stability, providing a new strategy for the optimization and application of AMPs.Copyright © 2024. Published by Elsevier Inc.

由于其独特的抗菌机制和广谱抗菌活性，抗菌肽（AMPs）作为一种极具潜力的抗菌替代品而备受关注。Anoplin是一种源自独居胡蜂Anoplius samariensis毒囊的天然抗菌肽，具有广谱抗菌活性、低溶血活性和低耐药性等特点。然而，其相对温和的抗菌效力和较差的稳定性限制了其进一步的开发和应用。本研究首次将全氟芳基半胱氨酸或十氟联苯半胱氨酸作为肽链交联剂应用于Anoplin，成功制备了一系列构象受限的肽类似物。结果表明，这些交联肽不仅在生理盐浓度下保持了抗菌活性，而且在血清中也表现出高效的抗菌效果，同时还提高了对酶降解的抵抗力。特别是，Ano-(3-10)表现出增强的广谱抗菌活性、低溶血毒性，并且在生理盐浓度和蛋白水解条件下均有效。机制研究表明，这些衍生物通过破坏细菌外膜的完整性，最终导致膜崩解，从而发挥快速抗菌作用。此外，这些类似物还能有效抑制生物膜的形成。在一系列传代实验中，大肠杆菌和金黄色葡萄球菌在15代传代后均未对Ano-(3-10)产生耐药性。总之，本研究成功开发了一类新型的具有强效抗菌活性和高蛋白水解稳定性的环状抗菌肽类似物，为抗菌肽的优化和应用提供了一种新的策略。版权所有 © 2024。由Elsevier Inc.出版。

Links

http://www.ncbi.nlm.nih.gov/pubmed/41980345
http://dx.doi.org/10.1016/j.bioorg.2026.109851

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