4'-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication

Science. 2022 Jan 14;375(6577):161-167. doi: 10.1126/science.abj5508. Epub 2021 Dec 2.

Abstract

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and older adults. We describe 4′-fluorouridine (4′-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with high selectivity index in cells and human airway epithelia organoids. Polymerase inhibition within in vitro RNA-dependent RNA polymerase assays established for RSV and SARS-CoV-2 revealed transcriptional stalling after incorporation. Once-daily oral treatment was highly efficacious at 5 milligrams per kilogram (mg/kg) in RSV-infected mice or 20 mg/kg in ferrets infected with different SARS-CoV-2 variants of concern, initiated 24 or 12 hours after infection, respectively. These properties define 4′-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2, and related RNA virus infections.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Cell Line
  • Coronavirus RNA-Dependent RNA Polymerase / metabolism
  • Disease Models, Animal
  • Female
  • Ferrets
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Mononegavirales / drug effects
  • Mononegavirales / physiology
  • RNA-Dependent RNA Polymerase / metabolism
  • Respiratory Mucosa / virology
  • Respiratory Syncytial Virus Infections / drug therapy*
  • Respiratory Syncytial Virus Infections / virology
  • Respiratory Syncytial Virus, Human / drug effects*
  • Respiratory Syncytial Virus, Human / genetics
  • Respiratory Syncytial Virus, Human / physiology
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / physiology
  • Transcription, Genetic
  • Uracil Nucleotides / administration & dosage
  • Uracil Nucleotides / metabolism
  • Uracil Nucleotides / pharmacology*
  • Virus Replication / drug effects

Substances

  • 4'-fluorouridine
  • Antiviral Agents
  • Uracil Nucleotides
  • Coronavirus RNA-Dependent RNA Polymerase
  • RNA-Dependent RNA Polymerase