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Nature. 2020 Apr 9. doi: 10.1038/s41586-020-2223-y. [Epub ahead of print]
Structure of Mpro from COVID-19 virus and discovery of its inhibitors.
Jin Z1,2, Du X2, Xu Y3, Deng Y4, Liu M5, Zhao Y1, Zhang B1, Li X4, Zhang L5, Peng C6, Duan Y1, Yu J1, Wang L1, Yang K7, Liu F1, Jiang R5, Yang X5, You T1, Liu X1, Yang X1, Bai F1, Liu H3, Liu X8, Guddat LW9, Xu W1,6, Xiao G5, Qin C4, Shi Z5, Jiang H10,11, Rao Z12,13,14, Yang H15.
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Abstract
A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1-4. Currently there are no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these compounds inhibited Mpro with IC50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.
PMID:32272481DOI:10.1038/s41586-020-2223-y