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

Protein Cell. 2020 Oct;11(10):723-739. doi: 10.1007/s13238-020-00768-w. Epub 2020 Aug 4.

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 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: DHODH inhibitors; SARS-CoV-2; de novo pyrimidine biosynthesis; immuno-regulation; influenza viruses; virus replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Betacoronavirus / drug effects
  • Betacoronavirus / physiology
  • Binding Sites / drug effects
  • COVID-19
  • Cell Line
  • Coronavirus Infections / drug therapy*
  • 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 / antagonists & inhibitors*
  • Oxidoreductases / metabolism
  • Oxidoreductases Acting on CH-CH Group Donors
  • Pandemics*
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / virology
  • Protein Binding / drug effects
  • Pyrimidines / biosynthesis
  • RNA Viruses / drug effects*
  • RNA Viruses / physiology
  • SARS-CoV-2
  • Structure-Activity Relationship
  • Thiazoles / pharmacology*
  • Thiazoles / therapeutic use
  • Toluidines / pharmacology
  • Ubiquinone / metabolism
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Crotonates
  • DHODH inhibitor S312
  • DHODH inhibitor S416
  • Dihydroorotate Dehydrogenase
  • Hydroxybutyrates
  • Nitriles
  • Pyrimidines
  • Thiazoles
  • Toluidines
  • Ubiquinone
  • teriflunomide
  • Oseltamivir
  • Oxidoreductases
  • Oxidoreductases Acting on CH-CH Group Donors
  • Leflunomide