Structural basis for the inhibition of COVID-19 virus main protease by carmofur, an antineoplastic drug
Zhenming Jin, Yao Zhao, Yuan Sun, Bing Zhang, Haofeng Wang, Yan Wu, Yan Zhu, Chen Zhu, Tianyu Hu, Xiaoyu Du, Yinkai Duan, Jing Yu, Xiaobao Yang, Xiuna Yang, Xiang Liu, Luke W. Guddat, Gengfu Xiao, Lei
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-Å 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.
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