Journal article
High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors
Protein & cell, Vol.12(11), pp.877-888
11/01/2021
DOI: 10.1007/s13238-021-00836-9
PMCID: PMC8052528
PMID: 33864621
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 SARSCoV-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 substratebinding 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.
Details
- Title: Subtitle
- High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors
- Creators
- Yao Zhao - ShanghaiTech UniversityXiaoyu Du - Tsinghua UniversityYinkai Duan - ShanghaiTech UniversityXiaoyan Pan - Wuhan Institute of VirologyYifang Sun - Fudan UniversityTian You - ShanghaiTech UniversityLin Han - Fudan UniversityZhenming Jin - Tsinghua UniversityWeijuan Shang - Wuhan Institute of VirologyJing Yu - ShanghaiTech UniversityHangtian Guo - ShanghaiTech UniversityQianying Liu - Fudan UniversityYan Wu - Wuhan Institute of VirologyChao Peng - Shanghai Advanced Research InstituteJun Wang - ShanghaiTech UniversityChenghao Zhu - ShanghaiTech UniversityXiuna Yang - ShanghaiTech UniversityKailin Yang - Cleveland ClinicYing Lei - ShanghaiTech UniversityLuke W. Guddat - The University of QueenslandWenqing Xu - Shanghai Advanced Research InstituteGengfu Xiao - Wuhan Institute of VirologyLei Sun - Fudan UniversityLeike Zhang - Wuhan Institute of VirologyZihe Rao - Tsinghua UniversityHaitao Yang - ShanghaiTech University
- Resource Type
- Journal article
- Publication Details
- Protein & cell, Vol.12(11), pp.877-888
- DOI
- 10.1007/s13238-021-00836-9
- PMID
- 33864621
- PMCID
- PMC8052528
- NLM abbreviation
- Protein Cell
- ISSN
- 1674-800X
- eISSN
- 1674-8018
- Publisher
- Higher Education Press
- Language
- English
- Date published
- 11/01/2021
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696727202771
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