冠状病毒主蛋白酶功能及抑制剂筛选方法研究进展

Advances in coronavirus main protease functions and inhibitor screening methods

摘要:

冠状病毒是严重威胁人类与动物健康的病原体。主蛋白酶(main protease, Mpro)在病毒生命周期及宿主免疫调节中均发挥着重要作用，是开发广谱抗冠状病毒药物的关键靶点。Mpro的核心作用在于特异性切割病毒多聚蛋白pp1a和pp1ab，以释放功能性非结构蛋白(non-structural proteins, NSPs)，进而驱动病毒复制/转录复合体的组装。此外，Mpro能够靶向切割宿主免疫信号通路中的关键分子，有利于病毒实现免疫逃逸。鉴于其功能的双重性以及催化中心的高度保守性，针对Mpro的研究已成为该领域的热点。本文系统概述了Mpro的结构特征与功能多样性，重点论述了其在病毒复制周期中的催化机制及介导免疫抑制的作用，进而详细探讨了Mpro抑制剂的筛选方法与设计策略，为针对该靶点的抗冠状病毒药物研发提供了理论依据和新思路。

Abstract:

Coronaviruses pose a serious threat to human and animal health. Their main protease (Mpro) plays a critical role in both the viral life cycle and host immune regulation, serving as a key target for the development of broad-spectrum anti-coronavirus drugs. The core function of Mpro lies in its specific cleavage of viral polyproteins pp1a and pp1ab to release functional non-structural proteins (NSPs), thereby driving the assembly of the viral replication/transcription complex. Additionally, Mpro can target and cleave key molecules in host immune signaling pathways, facilitating viral immune evasion. Given its dual roles and highly conserved catalytic center, the research on Mpro has become a major focus in the field. This review systematically outlines the structural features and functional diversity of Mpro, with an emphasis on its catalytic mechanism in the viral replication cycle and its role in mediating immune suppression. Furthermore, this article details the screening methods and design strategies for Mpro inhibitors, aiming to offer theoretical foundations and novel insights for the development of anti-coronavirus drugs targeting this critical protein.