《生命科学》 2025, 37(7): 795-807

靶向新冠病毒3CL蛋白酶的新药研发进展

聂添情^1,2,3 , 熊慕雅⁴ , 苏海霞^1,5 , 许叶春^1,4,5,*

¹中国科学院上海药物研究所原创新药研究全国重点实验室，上海 201203 ²临港实验室，上海 200031 ³上海科技大学物质科学与技术学院，上海 201210 ⁴国科大杭州高等研究院药物与技术学院，杭州 310024 ⁵中国科学院大学，北京 100049

摘　要：

病毒基因组编码的蛋白酶作为病毒生命周期中不可或缺且高度保守的关键酶，已成为广谱抗病毒药物研发的核心靶点。自2019 年新型冠状病毒感染(COVID-19) 大流行以来，靶向新冠病毒3C 样蛋白酶(3C-like protease, 3CL^pro) 的抑制剂开发已成为抗新冠病毒药物研发的重要策略。蛋白酶晶体结构，尤其是其与抑制剂的复合物晶体结构的解析在蛋白酶抑制剂药物的研发过程中发挥了重要作用。因此，本文首先综述3CL^pro 的三维结构特征、底物特异性识别机制及进化保守特征，随后结合临床前及临床研究数据，重点剖析代表性药物的构效优化路径及抑制剂与3CL^pro 的互作模式演变，从而为靶向冠状病毒及其他病毒蛋白酶的新型抗病毒药物开发提供典型案例和方法借鉴，促进结构生物学在新药研发中的更广泛应用。

通讯作者：许叶春 , Email:ycxu@simm.ac.cn

Advances in drug development targeting SARS-CoV-2 3CL protease

NIE Tian-Qing^1,2,3 , XIONG Mu-Ya⁴ , SU Hai-Xia^1,5 , XU Ye-Chun^1,4,5,*

¹State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China ²Lingang Laboratory, Shanghai 200031, China ³School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China ⁴School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China ⁵University of Chinese Academy of Sciences, Beijing 100049, China

Abstract:

The protease encoded by the viral genome is an indispensable and highly conserved enzyme in the viral life cycle and has emerged as a critical target for the development of broad-spectrum antiviral drugs. Since the outbreak of the COVID-19 pandemic in 2019, the development of inhibitors targeting the 3C-like protease (3CL^pro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a crucial strategy in anti-SARSCoV-2 drug discovery. The crystal structure determination of protease and its conjugate with inhibitors in particular plays a pivotal role in the discovery and development of drugs against the protease. This article first reviews the  three-dimensional structural characteristics of 3C^Lpro, along with its substrate-specific recognition mechanisms and evolutionarily conserved features. Subsequently, by integrating preclinical and clinical data, we provide an in-depth analysis of the structure-activity optimization pathways of representative drugs and the evolution of inhibitor binding modes with 3CL^pro. Overall, this review aims to provide exemplary cases and methodological references for developing novel broad-spectrum antiviral agents targeting coronavirus proteases and other viral proteases, and to promote the wider application of structural biology in innovative drug discovery and development.

Communication Author：XU Ye-Chun , Email:ycxu@simm.ac.cn