SARS-CoV-2主蛋白酶耐药机制与抗耐药性药物化学策略

Drug Resistance Mechanisms of SARS-CoV-2 Main Protease and Chemical Strategies for Anti-Resistant Drugs

严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)主蛋白酶(main protease,M^(pro))在病毒复制周期中发挥关键作用,是抗新冠病毒药物的重要靶点。然而,病毒的快速变异引起了对M^(pro)抑制剂的耐药性问题,对全球公共卫生构成严重威胁。对SARS-CoV-2 M^(pro)的耐药机制进行总结,并探讨了新型抗耐药性抑制剂的设计策略。针对M^(pro)耐药突变对现有抑制剂疗效的影响,提出了多种基于靶标结构的抗耐药性药物设计方法,如多位点占据、变构位点开发、共价结合等策略,此外还探讨了蛋白降解靶向嵌合体(proteolytic targeting chimera,PROTAC)在降解病毒靶蛋白中的应用。为解决SARS-CoV-2 M^(pro)耐药性问题提供了新思路,并为未来可能出现的冠状病毒疫情提供药物筛选和开发的参考。

The SARS-CoV-2 main protease(M^(pro))plays a key role in the viral replication cycle,and is an important target for anti-SARS-Cov-2 drugs.However,the rapid mutation of the virus has led to drug resistance with M^(pro) inhibitors,posing a serious threat to global public health.This article summarizes the resistance mechanisms of SARS-CoV-2 M^(pro) and explores the strategies for the design of new anti-resistant inhibitors.By analyzing the impact of M^(pro) resistance mutations on the efficacy of existing inhibitors,we summarized various target structure-based anti-resistance drug design methods such as multi-site occupancy,allosteric site development,and covalent binding,and discussed the utility of PROTAC technology in degrading resistant viral proteins,aiming to provide innovative solutions to the drug resistance problem of SARS-CoV-2 M^(pro) and some reference for drug screening and development in response to potential future coronavirus pandemics.