Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2.

Rui Xiong; 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

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Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2.

Author: Rui XIONG ¹ ; Leike ZHANG ² ; Shiliang LI ¹ ; Yuan SUN ² ; Minyi DING ¹ ; Yong WANG ³ ; Yongliang ZHAO ³ ; Yan WU ² ; Weijuan SHANG ² ; Xiaming JIANG ² ; Jiwei SHAN ¹ ; Zihao SHEN ¹ ; Yi TONG ¹ ; Liuxin XU ¹ ; Yu CHEN ³ ; Yingle LIU ³ ; Gang ZOU ⁴ ; Dimitri LAVILLETE ⁴ ; Zhenjiang ZHAO ¹ ; Rui WANG ¹ ; Lili ZHU ¹ ; Gengfu XIAO ² ; Ke LAN ³ ; Honglin LI ⁵ ; Ke XU ⁶
Author Information

1. 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.
2. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
3. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, 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.
5. 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. hlli@ecust.edu.cn.
6. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China. xuke03@whu.edu.cn.
Publication Type:Journal Article
Keywords: DHODH inhibitors; SARS-CoV-2; de novo pyrimidine biosynthesis; immuno-regulation; influenza viruses; virus replication
MeSH: Animals; Antiviral Agents; pharmacology; therapeutic use; Betacoronavirus; drug effects; physiology; Binding Sites; drug effects; Cell Line; Coronavirus Infections; drug therapy; virology; Crotonates; pharmacology; Cytokine Release Syndrome; drug therapy; Drug Evaluation, Preclinical; Gene Knockout Techniques; Humans; Influenza A virus; drug effects; Leflunomide; pharmacology; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; drug therapy; Oseltamivir; therapeutic use; Oxidoreductases; antagonists & inhibitors; metabolism; Pandemics; Pneumonia, Viral; drug therapy; virology; Protein Binding; drug effects; Pyrimidines; biosynthesis; RNA Viruses; drug effects; physiology; Structure-Activity Relationship; Toluidines; pharmacology; Ubiquinone; metabolism; Virus Replication; drug effects
From: Protein & Cell 2020;11(10):723-739
CountryChina
Language:English
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 broad-spectrum 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 EC 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.