抗菌肽构效关系解析及分子设计研究进展

Research advances in structure-activity relationship analysis and molecular design of antimicrobial peptides

摘要

细菌耐药性持续加剧，开发新型、安全且高效的抗菌剂已成为生命科学和农业领域亟待解决的重要问题。抗菌肽（antimicrobial peptides，AMP）作为天然免疫系统的重要效应分子，因兼具广谱抗菌、免疫调节及较低耐药诱导风险等优势，被视为传统抗生素的潜在替代品。然而，抗菌效能、生物安全性、体内稳定性和规模化制备成本等问题，仍是制约其应用的关键瓶颈。本文系统综述了 AMP 的理化特性与构效关系，重点解析了净电荷、疏水性、两亲性等核心参数对 AMP 生物学功能的影响，概述了 AMP 发挥抗菌、抗生物被膜和免疫调节作用的分子机制，系统总结了基于构效关系的序列优化、化学修饰、环化与二聚化、纳米化改造以及人工智能辅助设计和高通量筛选等 AMP 优化与设计策略，概述了原核与真核表达系统在 AMP 制备中的应用，总结了 AMP 在畜牧业等多领域应用的研究进展，并对 AMP 未来发展方向进行了展望，旨在为高效、安全 AMP 的理性设计、规模化制备及应用转化提供参考。

Abstract

The escalating crisis of bacterial resistance has made the development of novel, safe, and highly effective antimicrobial agents a critical challenge in the life sciences and agricultural sectors. Antimicrobial peptides (AMP), as essential effector molecules of the innate immune system, are regarded as promising alternatives to conventional antibiotics due to their broad-spectrum antimicrobial activity, immunomodulatory properties, and relatively low risk of inducing drug resistance. However, challenges related to antimicrobial efficacy, biosafety, in vivo stability and the cost of large-scale production remain key bottlenecks restricting their practical application. This review systematically summarizes the physicochemical properties and structure-activity relationships of AMP, with particular emphasis on elucidating the effects of core parameters such as charge, hydrophobicity, and amphipathicity on their biological functions. The molecular mechanisms underlying the antimicrobial, antibiofilm, and immunomodulatory activities of AMP are also discussed. Furthermore, this article comprehensively reviewed strategies for AMP optimization and design based on structure-activity relationships, including sequence optimization, chemical modification, cyclization and dimerization, nanoengineering, artificial intelligence-assisted design, and high-throughput screening. The applications of prokaryotic and eukaryotic expression systems for AMP preparation are outlined, and recent advances in their application in animal husbandry and other fields are highlighted. Finally, future directions for AMP research and development are discussed. This review aims to provide a reference for the rational design, scalable production, and translational application of safe and highly effective AMP.

关键词

抗菌肽 / 构效关系 / 分子设计 / 人工智能 / 表达与应用

Key words

antimicrobial peptides / structure-activity relationships / molecular design / artificial intelligence / expression and application

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基金资助

国家自然科学基金区域创新发展联合基金重点项目(U25A20708)

国家自然科学基金项目(32272914)

国家重点研发计划项目(2022YFD1300700)