An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

Sci Transl Med. 2020 Apr 29;12(541):eabb5883. doi: 10.1126/scitranslmed.abb5883. Epub 2020 Apr 6.

Abstract

Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Here, we show that the ribonucleoside analog β-d-N4-hydroxycytidine (NHC; EIDD-1931) has broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs, as well as increased potency against a CoV bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC prodrug (β-d-N4-hydroxycytidine-5'-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple CoVs and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / administration & dosage
  • Adenosine Monophosphate / analogs & derivatives
  • Alanine / administration & dosage
  • Alanine / analogs & derivatives
  • Animals
  • Antibiotic Prophylaxis
  • Antiviral Agents / administration & dosage*
  • Betacoronavirus / physiology
  • COVID-19
  • Cell Line
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / pathology
  • Cytidine / administration & dosage
  • Cytidine / analogs & derivatives
  • Disease Models, Animal
  • Drug Resistance, Viral
  • Humans
  • Hydroxylamines
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Middle East Respiratory Syndrome Coronavirus / physiology
  • Models, Molecular
  • Mutation / drug effects
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / pathology
  • Primary Cell Culture
  • RNA, Viral
  • RNA-Dependent RNA Polymerase / chemistry
  • RNA-Dependent RNA Polymerase / genetics
  • Random Allocation
  • Respiratory System / cytology
  • Ribonucleosides / administration & dosage*
  • SARS-CoV-2
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Hydroxylamines
  • RNA, Viral
  • Ribonucleosides
  • N(4)-hydroxycytidine
  • remdesivir
  • Adenosine Monophosphate
  • Cytidine
  • RNA-Dependent RNA Polymerase
  • Alanine
  • molnupiravir