3.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
Protein & Cell 2023;14(1):17-27
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.
Humans
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Antiviral Agents/chemistry*
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COVID-19
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COVID-19 Drug Treatment
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High-Throughput Screening Assays
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Molecular Docking Simulation
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Protease Inhibitors/chemistry*
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SARS-CoV-2/enzymology*
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Viral Nonstructural Proteins
Result Analysis
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