Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged co
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Protein & Cell
RESEARCH ARTICLE
Rui Xiong2, Leike Zhang3, Shiliang Li2 , Yuan Sun3, Minyi Ding2, Yong Wang1, Yongliang Zhao1, Yan Wu3, Weijuan Shang3, Xiaming Jiang3, Jiwei Shan2, Zihao Shen2, Yi Tong2, Liuxin Xu2, Yu Chen1, Yingle Liu1, Gang Zou4, Dimitri Lavillete4, Zhenjiang Zhao2, Rui Wang2, Lili Zhu2 , Gengfu Xiao3, Ke Lan1 Honglin Li2& , Ke Xu1,4& 1
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China 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 & Correspondence: [email protected] (H. Li), [email protected] (K. Xu) Received February 15, 2020 Accepted July 5, 2020 2
ABSTRACT Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV2. 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 Rui Xiong, Leike Zhang, and Shiliang Li contribute equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13238-020-00768-w) contains supplementary material, which is available to authorized users.
© The Author(s) 2020
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 INTRODUCTION Acute viral infections, such as influenza virus, SARS-CoV, MERS-CoV, Ebola virus, Zika virus, and the very recent SARS-CoV-2 are an increasing and probably lasting global threat (Gao, 2018). Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Broad-spectrum antivirals (BSA) are clinically needed for the effective control of emerging and re-emerging v
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