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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Acknowledgements
This work was supported by the Science and Technology Commission of Shanghai Municipality grants (Grant IDs: 20431900102, 20431900100, and 20430780300); Shanghai Science and Technology Development Funds (Grant ID: 20QA1406400); the Youth Innovation Promotion Association CAS (grants 2018367 to L.-K.Z). the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (Grant ID: 2018ZX09711002); National Natural Science Foundation of China (No. 82003654); as well as the start-up package from ShanghaiTech University.
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PXR, LW, BQL, HLL, HLJ, and FB performed computational simulations and analysis. HG, XLZ, and LLZ performed the SPR assays and did the analysis. WCY, YCX, and EHX prepared the protein and RNA samples, performed the experimental validations with the other members. WJS and LKZ performed antiviral activities measurement in cells. All the authors were involved in writing the manuscripts.
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Ren, Px., Shang, Wj., Yin, Wc. et al. A multi-targeting drug design strategy for identifying potent anti-SARS-CoV-2 inhibitors. Acta Pharmacol Sin 43, 483–493 (2022). https://doi.org/10.1038/s41401-021-00668-7
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DOI: https://doi.org/10.1038/s41401-021-00668-7
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