Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics |
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Authors: | Kao Richard Y Tsui Wayne H W Lee Terri S W Tanner Julian A Watt Rory M Huang Jian-Dong Hu Lihong Chen Guanhua Chen Zhiwei Zhang Linqi He Tian Chan Kwok-Hung Tse Herman To Amanda P C Ng Louisa W Y Wong Bonnie C W Tsoi Hoi-Wah Yang Dan Ho David D Yuen Kwok-Yung |
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Institution: | Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. ryykao@hkucc.hku.hk |
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Abstract: | The severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infected more than 8,000 people across 29 countries and caused more than 900 fatalities. Based on the concept of chemical genetics, we screened 50,240 structurally diverse small molecules from which we identified 104 compounds with anti-SARS-CoV activity. Of these 104 compounds, 2 target the SARS-CoV main protease (M(pro)), 7 target helicase (Hel), and 18 target spike (S) protein-angiotensin-converting enzyme 2 (ACE2)-mediated viral entry. The EC(50) of the majority of the 104 compounds determined by SARS-CoV plaque reduction assay were found to be at low micromolar range. Three selected compounds, MP576, HE602, and VE607, validated to be inhibitors of SARS-CoV M(pro), Hel, and viral entry, respectively, exhibited potent antiviral activity (EC(50) < 10 microM) and comparable inhibitory activities in target-specific in vitro assays. |
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