High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors

  • Protein Cell. 2022 Sep 28;14(1):17-27. doi: 10.1093/procel/pwac016.
Yi Zang  1  2  3 ,  Mingbo Su  4 ,  Qingxing Wang  5  6 ,  Xi Cheng  2  3 ,  Wenru Zhang  4 ,  Yao Zhao  7 ,  Tong Chen  2  5 ,  Yingyan Jiang  1 ,  Qiang Shen  1 ,  Juan Du  3 ,  Qiuxiang Tan  2 ,  Peipei Wang  1  2 ,  Lixin Gao  1  2 ,  Zhenming Jin  7 ,  Mengmeng Zhang  1  2 ,  Cong Li  1  2 ,  Ya Zhu  2 ,  Bo Feng  1  2 ,  Bixi Tang  1  2 ,  Han Xie  2 ,  Ming-Wei Wang  1  2  5 ,  Mingyue Zheng  2  3  5 ,  Xiaoyan Pan  6 ,  Haitao Yang  7 ,  Yechun Xu  2  3  5 ,  Beili Wu  2  3  5  8 ,  Leike Zhang  6 ,  Zihe Rao  7 ,  Xiuna Yang  7 ,  Hualiang Jiang  2  3  5 ,  Gengfu Xiao  6 ,  Qiang Zhao  2  3  8  9 ,  Jia Li  1  2  3  4  9
Affiliations
  • 1. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
  • 4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China.
  • 7. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 8. CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China.
  • 9. Zhongshan Branch, the Institute of Drug Discovery and Development, Chinese Academy of Sciences, Guangdong 528400, China.
PMID: 36726755 DOI: 10.1093/procel/pwac016
Abstract

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in Antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.

Keywords
CoV-2; SARS; high-throughput screening; main; papain-like; proteases.
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