Abstract
A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three “hot” spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.
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1 ShanghaiTech University, Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879)
2 Tsinghua University, Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178)
3 Chinese Academy of Sciences, State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Wuhan, China (GRID:grid.9227.e) (ISNI:0000000119573309)
4 Fudan University, The Fifth People’s Hospital of Shanghai, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443)
5 ShanghaiTech University, Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879); Tsinghua University, Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178)
6 Chinese Academy of Science, Zhangjiang Lab, National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309)
7 Cleveland Clinic, Taussig Cancer Center, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725)
8 The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537)
9 ShanghaiTech University, Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879); Chinese Academy of Science, Zhangjiang Lab, National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309)