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

Yi Zang; Mingbo SU; Qingxing Wang; Xi Cheng; Wenru Zhang; Yao Zhao; Tong Chen; Yingyan Jiang; Qiang Shen; Juan DU; Qiuxiang Tan; Peipei Wang; Lixin Gao; Zhenming Jin; Mengmeng Zhang; Cong LI; Ya Zhu; Bo Feng; Bixi Tang; Han Xie; Ming-wei Wang; Mingyue Zheng; Xiaoyan Pan; Haitao Yang; Yechun XU; Beili WU; Leike Zhang; Zihe Rao; Xiuna Yang; Hualiang Jiang; Gengfu Xiao; Qiang Zhao; Jia LI

Return

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

Author: Yi ZANG ¹ ; Mingbo SU ² ; Qingxing WANG ³ ; Xi CHENG ⁴ ; Wenru ZHANG ² ; Yao ZHAO ⁵ ; Tong CHEN ⁴ ; Yingyan JIANG ¹ ; Qiang SHEN ¹ ; Juan DU ⁶ ; Qiuxiang TAN ⁴ ; Peipei WANG ¹ ; Lixin GAO ¹ ; Zhenming JIN ⁵ ; Mengmeng ZHANG ¹ ; Cong LI ¹ ; Ya ZHU ⁴ ; Bo FENG ¹ ; Bixi TANG ¹ ; Han XIE ⁴ ; Ming-Wei WANG ¹ ; Mingyue ZHENG ⁴ ; Xiaoyan PAN ⁷ ; Haitao YANG ⁵ ; Yechun XU ⁴ ; Beili WU ⁴ ; Leike ZHANG ⁷ ; Zihe RAO ⁵ ; Xiuna YANG ⁵ ; Hualiang JIANG ⁴ ; Gengfu XIAO ⁷ ; Qiang ZHAO ⁴ ; Jia LI ¹
Author Information

1. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
2. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
3. University of Chinese Academy of Sciences, Beijing 100049, China.
4. 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.
5. Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
6. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
7. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: CoV-2; SARS; high-throughput screening; main; papain-like; proteases
MeSH: Humans; Antiviral Agents/chemistry*; COVID-19; COVID-19 Drug Treatment; High-Throughput Screening Assays; Molecular Docking Simulation; Protease Inhibitors/chemistry*; SARS-CoV-2/enzymology*; Viral Nonstructural Proteins
From: Protein & Cell 2023;14(1):17-27
CountryChina
Language:English
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 (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro 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.