1. High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.
- Author
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Zang, Yi, Su, Mingbo, Wang, Qingxing, Cheng, Xi, Zhang, Wenru, Zhao, Yao, Chen, Tong, Jiang, Yingyan, Shen, Qiang, Du, Juan, Tan, Qiuxiang, Wang, Peipei, Gao, Lixin, Jin, Zhenming, Zhang, Mengmeng, Li, Cong, Zhu, Ya, Feng, Bo, Tang, Bixi, and Xie, Han
- 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 (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. [ABSTRACT FROM AUTHOR]- Published
- 2023
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