SARS-CoV-2主蛋白酶耐药机制与抗耐药性药物化学策略

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中文摘要：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，Mpro)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Mpro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 Mpro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Mpro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 Mpro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。

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

外文摘要：The SARS-CoV-2 main protease(Mpro)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 Mpro inhibitors,posing a serious threat to global public health.This article summarizes the resistance mechanisms of SARS-CoV-2 Mpro and explores the strategies for the design of new anti-resistant inhibitors.By analyzing the impact of Mpro 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 Mpro and some reference for drug screening and development in response to potential future coronavirus pandemics.

外文关键词：

SARS-CoV-2main proteasedrug resistance mechanismanti-resistant drug designPROTAC

作者：

谷漫玉、叶冰、高升华、展鹏、刘新泳

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作者单位：

山东大学药学院药物化学研究所化学生物学教育部重点实验室,山东济南 250012

关键词：

严重急性呼吸综合征冠状病毒2 主蛋白酶耐药机制抗耐药性药物设计蛋白降解靶向嵌合体

出版年：

2024

DOI：