High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors

• DOI: 10.1007/s13238-021-00836-9
• Publication Date: 2021-04-17T10:03:11Z
• Authors: Yao Zhao; Xiaoyu Du; Yinkai Duan; Xiaoyan Pan; Yifang Sun; Tian You; Lin Han; Zhenming Jin; Weijuan Shang; Jing Yu; Hangtian Guo; Qianying Liu; Yan Wu; Chao Peng; Jun Wang; Chenghao Zhu; Xiuna Yang; Kailin Yang; Ying Lei; Luke W. Guddat; Wenqing Xu; Gengfu Xiao; Lei Sun; Leike Zhang; Zihe Rao; Haitao Yang
• Keywords: ISG15; Drug repositioning; Iminosugar; Drug Development; Approved drug

Abstract A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for COVID-19 outbreak. Currently, effective treatment options remain very limited this disease; therefore, there is an urgent need to identify anti-COVID-19 agents. In study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active leads target SARS-CoV-2 papain-like protease (PLpro). Together with main (M pro ), PLpro responsible processing viral replicase polyprotein into functional units. Therefore, it attractive antiviral development. Here discovered four compounds, YM155, cryptotanshinone, tanshinone I GRL0617 inhibit IC 50 values ranging from 1.39 5.63 μmol/L. These also exhibit strong activities cell-based assays. anticancer candidate most potent activity EC value of 170 nmol/L. addition, have determined crystal structures enzyme its complex revealing a unique binding mode. YM155 simultaneously targets three “hot” spots on PLpro, including substrate-binding pocket, interferon stimulating gene product 15 (ISG15) site zinc finger motif. Our results demonstrate efficacy screening repurposing strategy, which led discovery potential treatments.