Structural basis for the inhibition of COVID-19 virus main protease by carmofur, an antineoplastic drug
Structural basis for the inhibition of COVID-19 virus main protease by carmofur, an antineoplastic drug
Abstract COVID-19 virus is the cause of a debilitating and life-threatening infectious pulmonary disease that is now responsible for a global pandemic. Currently, there are no specific drugs or vaccines to contain this virus. The main protease (Mpro) of COVID-19 virus is a key enzyme, which plays an essential role in viral replication and transcription, making it an ideal drug target. An FDA-approved antineoplastic drug, carmofur, has been identified as an inhibitor that targets COVID-19 virus Mpro. However, its inhibitory mechanism is unknown. Here, we report the 1.6-? crystal structure of COVID-19 virus Mpro in complex with carmofur. The crystal structure shows that carmofur contains an electrophilic carbonyl reactive group, which covalently binds to C145, a member of the catalytic dyad. As a result, its fatty acid tail occupies the hydrophobic S2 subsite of Mpro whilst its 5-fluorouracil head is cleaved as product of the new covalent bond that has formed. Carmofur is active in a cell based antiviral assay with an EC50 of 24.87 μM. It is therefore a promising lead compound for the development of new antivirals to target COVID-19.
Yang Haitao、Sun Yuan、Zhu Yan、Zhu Chen、Yang Xiuna、Liu Xiang、Xiao Gengfu、Hu Tianyu、Wu Yan、Guddat Luke W.、Yang Xiaobao、Rao Zihe、Wang Haofeng、Yu Jing、Jin Zhenming、Zhang Leike、Zhao Yao、Duan Yinkai、Du Xiaoyu、Zhang Bing
Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityState Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of SciencesShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityState Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai UniversityState Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of SciencesShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityState Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of SciencesSchool of Chemistry and Molecular Biosciences, the University of QueenslandShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University||Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University||State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Response, College of Life Sciences, College of Pharmacy, Nankai UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University||School of Life Sciences, Tianjin UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University||Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua UniversityState Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of SciencesShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University||Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua UniversityShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University
基础医学药学分子生物学
Yang Haitao,Sun Yuan,Zhu Yan,Zhu Chen,Yang Xiuna,Liu Xiang,Xiao Gengfu,Hu Tianyu,Wu Yan,Guddat Luke W.,Yang Xiaobao,Rao Zihe,Wang Haofeng,Yu Jing,Jin Zhenming,Zhang Leike,Zhao Yao,Duan Yinkai,Du Xiaoyu,Zhang Bing.Structural basis for the inhibition of COVID-19 virus main protease by carmofur, an antineoplastic drug[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/2020.04.09.033233.点此复制
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