Volume 12 Issue 11
Nov.  2021
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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. High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors[J]. Protein&Cell, 2021, 12(11): 876-887. doi: 10.1007/s13238-021-00836-9
Citation: 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. High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors[J]. Protein&Cell, 2021, 12(11): 876-887. doi: 10.1007/s13238-021-00836-9

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

doi: 10.1007/s13238-021-00836-9
Funds:

Project of International Cooperation and Exchanges NSFC (Grant No. 81520108019 to Z.R.)

Youth Program of NSFC (Grant No. 81900729 to L.S.).

Science and Technology Commission of Shanghai Municipality (Grant No. 20431900200 to H.Y.)

We are grateful to Juan Kong for high-throughput screening technical support. This research was funded by National Key R&D Program of China grants 2017YFC0840300 (Z.R.) and 2020YFA0707500 (H.Y.)

Department of Science and Technology of Guangxi Zhuang Autonomous Region (Grant No. 2020AB40007 to X.Y.)

Hubei Science and Technology Project (Grant No. 2020FCA003 to L.Z.)

  • Received Date: 2020-11-20
  • Rev Recd Date: 2021-02-05
  • 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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