Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2.
Author(s) Xiong R; Zhang L; Li S; Sun Y; Ding M; Wang Y; Zhao Y; Wu Y; Shang W; Jiang X; Shan J; Shen Z; Tong Y; Xu L; Chen Y; Liu Y; Zou G; Lavillete D; Zhao Z; Wang R; Zhu L; Xiao G; Lan K; Li H; Xu K
Publication year 2020
Publication name Protein & cell [Protein Cell] 2020 Oct; Vol. 11 (10), pp. 723-739. Date of Electronic Publication:
Material typeAcademic journal
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 50 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.
Keyword(s)Animals, Antiviral Agents therapeutic use, Betacoronavirus drug effects, Betacoronavirus physiology, Binding Sites drug effects, COVID-19, Cell Line, Coronavirus Infections virology, Crotonates pharmacology, Cytokine Release Syndrome drug therapy, Dihydroorotate Dehydrogenase, Drug Evaluation, Preclinical, Gene Knockout Techniques, Humans, Hydroxybutyrates, Influenza A virus drug effects, Leflunomide pharmacology, Mice, Mice, Inbred BALB C, Nitriles, Orthomyxoviridae Infections drug therapy, Oseltamivir therapeutic use, Oxidoreductases metabolism, Oxidoreductases Acting on CH-CH Group Donors, Pneumonia, Viral virology, Protein Binding drug effects, Pyrimidines biosynthesis, RNA Viruses physiology, SARS-CoV-2, Structure-Activity Relationship, Thiazoles therapeutic use, Toluidines pharmacology, Ubiquinone metabolism, Virus Replication drug effects, Antiviral Agents pharmacology, Coronavirus Infections drug therapy, Oxidoreductases antagonists & inhibitors, Pandemics, Pneumonia, Viral drug therapy, RNA Viruses drug effects, Thiazoles pharmacology