Leike Zhang
Shiliang Li
Yuan Sun
Minyi Ding
Yong Wang
Yongliang Zhao
Yan Wu
Weijuan Shang
Xiaming Jiang
Jiwei Shan
Zihao Shen
Yi Tong
Liuxin Xu
Yu Chen
Yingle Liu
Gang Zou
Dimitri Lavillete
Zhenjiang Zhao
Rui Wang
Lili Zhu
Gengfu Xiao
Ke Lan
Honglin Li
Ke Xu
1 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China;
2 Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;
3 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China;
4 CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Funds: This work was supported in part by the National Key Research and Development Program Grants (2018FYA0900801 and 2018ZX10101004003001 to K.X., 2016YFA0502304 to H.L.), the National Natural Science Foundation of China (Grants 31922004 and 81772202 to K.X., 81825020 to H.L.), the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” of China (Grant 2018ZX09711002 to H.L.), Application & Frontier Research Program of Wuhan Government (2019020701011463 to K.X.).
Received Date: 2020-06-29
Rev Recd Date:2020-07-05
Publish Date:2020-09-27
Abstract
Abstract
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broadspectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.Keywords: de novo pyrimidine biosynthesis,
DHODH inhibitors,
SARS-CoV-2,
influenza viruses,
virus replication,
immuno-regulation
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