新型冠状病毒3CL蛋白酶抑制剂研究进展

Research Progress of SARS-CoV-23C-like Protease Inhibitors

新型冠状病毒肺炎(COVID-19)是继2003-SARS和2012-MERS之后又一高传染性、高致病性的冠状病毒肺炎,对人类健康、社会稳定和经济发展构成了严重威胁。在新冠病毒的众多靶点中,3CL蛋白酶(3CL^(pro)、3C样蛋白酶,也称作主要蛋白酶M pro)由于在子代病毒的复制和转录过程中极其关键的作用而备受研究人员的关注。3CL蛋白酶在多种冠状病毒及新冠病毒变异株中具有高度的结构相似性和保守性,是冠状病毒靶向药物研发最具吸引力的靶标之一。目前,国内外医药公司和科研机构针对此靶点进行了大量的药物研究开发。本研究针对已上市及处于临床试验阶段的3CL蛋白酶抑制剂进行分类总结,重点对构效关系进行探讨,并对其临床试验阶段的有效性及安全性等进行详细介绍;在总结天然产物来源的3CL蛋白酶抑制剂的基础上,大量研究和实验数据表明天然产物具有潜在的抗新冠病毒活性,但其有效性和安全性均需进一步研究验证。同时,将本课题组3CL蛋白酶抑制剂及蛋白水解靶向嵌合体(PROTACs)研发工作的代表性成果首次予以披露,以期为开发安全高效的抗新冠病毒感染药物提供参考。

Corona virus disease 2019(COVID-19)is a highly infectious and pathogenic coronavirus pneumonia after 2003-SARS and 2012-MERS,which has posed a serious threat to human health,social stability and economic development.Among the many therapeutic targets of SARS-CoV-2,3C-like protease(3CL^(pro),also known as the main protease M^(pro)has attracted much attention because of its crucial role in the replication and transcription of progeny viruses.3C-like protease has high structural similarity and conservation in many coronaviruses and SARS-CoV-2 variant strains,which is one of the most attractive targets for coronaviruses targeted drug research and development.At present,domestic and foreign pharmaceutical companies and scientific research institutions have carried out a large number of drug research and development for this target.We classified and summarized the 3C-like protease inhibitors that have been listed and in clinical trials,focusing on analysis of the structure-activity relationship,and introduced their effectiveness and safety in clinical trials in detail.This study also summarized 3C-like protease inhibitors from natural products.A large number of research and experimental data showed that natural products have potential anti-COVID-19 drugs activity,but their effectiveness and safety need further study and verification.At the same time,the representative achievements of the research and development of 3C-like protease inhibitors and proteolysis targeted chimeras(PROTACs)in our research group were disclosed for the first time in order to provide reference for developing safe and efficient anti-COVID-19 drugs.