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Abstract
The COVID-19, caused by SARS-CoV-2, is threatening public health, and there is no effective treatment. In this study, we have implemented a multi-targeted anti-viral drug design strategy to discover highly potent SARS-CoV-2 inhibitors, which simultaneously act on the host ribosome, viral RNA as well as RNA-dependent RNA polymerases, and nucleocapsid protein of the virus, to impair viral translation, frameshifting, replication, and assembly. Driven by this strategy, three alkaloids, including lycorine, emetine, and cephaeline, were discovered to inhibit SARS-CoV-2 with EC50 values of low nanomolar levels potently. The findings in this work demonstrate the feasibility of this multi-targeting drug design strategy and provide a rationale for designing more potent anti-virus drugs.
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1 ShanghaiTech University, School of Life Science and Technology, and Shanghai Institute for Advanced Immunochemical Studies, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879)
2 Chinese Academy of Sciences, State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Wuhan, China (GRID:grid.9227.e) (ISNI:0000000119573309)
3 Chinese Academy of Sciences, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309)
4 East China University of Science and Technology, State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, Shanghai, China (GRID:grid.28056.39) (ISNI:0000 0001 2163 4895)
5 ShanghaiTech University, School of Life Science and Technology, and Shanghai Institute for Advanced Immunochemical Studies, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879); Department of Chemistry, Imperial College London, London, United Kingdom (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111)
6 Chinese Academy of Sciences, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419)
7 ShanghaiTech University, School of Life Science and Technology, and Shanghai Institute for Advanced Immunochemical Studies, Shanghai, China (GRID:grid.440637.2) (ISNI:0000 0004 4657 8879); Chinese Academy of Sciences, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419)