A multi-targeting drug design strategy for identifying potent anti-SARS-CoV-2 inhibitors
Peng-xuan Ren1,
Wei-juan Shang2,
Wan-chao Yin3,
Huan Ge4,
Lin Wang1,
Xiang-lei Zhang1,
Bing-qian Li1,5,
Hong-lin Li4,
Ye-chun Xu3,
Eric H. Xu3,
Hua-liang Jiang1,3,
Li-li Zhu4,
Lei-ke Zhang2,
Fang Bai1
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 and 6University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Li-li Zhu: zhulfl@ecust.edu.cn, Lei-ke Zhang: zhangleike@wh.iov.cn, Fang Bai: baifang@shanghaitech.edu.cn,
DOI: 10.1038/s41401-021-00668-7
Received: 12 January 2021
Accepted: 22 March 2021
Advance online: 27 April 2021
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:
SARS-CoV-2 inhibitors; RdRp; host ribosome; Virus RNA
