1.High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors.
Yao ZHAO ; Xiaoyu DU ; Yinkai DUAN ; Xiaoyan PAN ; Yifang SUN ; Tian YOU ; Lin HAN ; Zhenming JIN ; Weijuan SHANG ; Jing YU ; Hangtian GUO ; Qianying LIU ; Yan WU ; Chao PENG ; Jun WANG ; Chenghao ZHU ; Xiuna YANG ; Kailin YANG ; Ying LEI ; Luke W GUDDAT ; Wenqing XU ; Gengfu XIAO ; Lei SUN ; Leike ZHANG ; Zihe RAO ; Haitao YANG
Protein & Cell 2021;12(11):877-888
A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M
Antiviral Agents/therapeutic use*
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Binding Sites
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COVID-19/virology*
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Coronavirus Papain-Like Proteases/metabolism*
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Crystallography, X-Ray
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Drug Evaluation, Preclinical
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Drug Repositioning
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High-Throughput Screening Assays/methods*
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Humans
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Imidazoles/therapeutic use*
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Inhibitory Concentration 50
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Molecular Dynamics Simulation
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Mutagenesis, Site-Directed
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Naphthoquinones/therapeutic use*
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Protease Inhibitors/therapeutic use*
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Protein Structure, Tertiary
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Recombinant Proteins/isolation & purification*
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SARS-CoV-2/isolation & purification*
2.Correction to: 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
Protein & Cell 2021;12(1):76-80
3.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
Protein & Cell 2020;11(10):723-739
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.
Animals
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Antiviral Agents
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pharmacology
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therapeutic use
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Betacoronavirus
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drug effects
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physiology
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Binding Sites
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drug effects
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Cell Line
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Coronavirus Infections
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drug therapy
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virology
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Crotonates
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pharmacology
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Cytokine Release Syndrome
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drug therapy
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Drug Evaluation, Preclinical
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Gene Knockout Techniques
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Humans
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Influenza A virus
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drug effects
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Leflunomide
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pharmacology
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Mice
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Mice, Inbred BALB C
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Orthomyxoviridae Infections
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drug therapy
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Oseltamivir
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therapeutic use
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Oxidoreductases
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antagonists & inhibitors
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metabolism
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Pandemics
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Pneumonia, Viral
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drug therapy
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virology
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Protein Binding
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drug effects
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Pyrimidines
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biosynthesis
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RNA Viruses
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drug effects
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physiology
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Structure-Activity Relationship
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Toluidines
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pharmacology
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Ubiquinone
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metabolism
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Virus Replication
;
drug effects
4.Correction to: 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 LAVILLETTE ; Zhenjiang ZHAO ; Rui WANG ; Lili ZHU ; Gengfu XIAO ; Ke LAN ; Honglin LI ; Ke XU
Protein & Cell 2022;13(10):778-778