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  3. A multi-targeting drug design strategy for identifying potent anti-SARS-CoV-2 inhibitors

A multi-targeting drug design strategy for identifying potent anti-SARS-CoV-2 inhibitors

  • Acta Pharmacol Sin. 2022 Feb;43(2):483-493. doi: 10.1038/s41401-021-00668-7.
Peng-Xuan Ren  # 1,  Wei-Juan Shang  # 2,  Wan-Chao Yin  # 3,  Huan Ge  # 4,  Lin Wang  # 1,  Xiang-Lei Zhang 1,  Bing-Qian Li 1 5,  Hong-Lin Li 4,  Ye-Chun Xu 3 6,  Eric H Xu 3 6,  Hua-Liang Jiang 1 3 6,  Li-Li Zhu 7,  Lei-Ke Zhang 8,  Fang Bai 9
Affiliations

Affiliations

  • 1 School of Life Science and Technology, and Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
  • 2 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
  • 3 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • 5 Department of Chemistry, Imperial College London, London, United Kingdom.
  • 6 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 7 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. [email protected].
  • 8 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China. [email protected].
  • 9 School of Life Science and Technology, and Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • # Contributed equally.
PMID: 33907306 DOI: 10.1038/s41401-021-00668-7
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.

Keywords

RdRp; SARS-CoV-2 inhibitors; Virus RNA; host ribosome.

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