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.
Julien Sourimant  1 ,  Carolin M Lieber  1 ,  Megha Aggarwal  1 ,  Robert M Cox  1 ,  Josef D Wolf  1 ,  Jeong-Joong Yoon  1 ,  Mart Toots  1 ,  Chengin Ye  2 ,  Zachary Sticher  3 ,  Alexander A Kolykhalov  3  4 ,  Luis Martinez-Sobrido  2 ,  Gregory R Bluemling  3  4 ,  Michael G Natchus  3 ,  George R Painter  3  4  5 ,  Richard K Plemper  1  6
Affiliations
  • 1. Center for Translational Antiviral Research, Georgia State University, Atlanta, GA 30303, USA.
  • 2. Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
  • 3. Emory Institute for Drug Development, Emory University, Atlanta, GA 30322, USA.
  • 4. Drug Innovation Ventures at Emory (DRIVE), Atlanta, GA 30322, USA.
  • 5. Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
  • 6. Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
PMID: 34855509 DOI: 10.1126/science.abj5508
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.

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