Language

English

Publication Date

7-11-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-61595-3

PMID

40645925

PMCID

PMC12254204

PubMedCentral® Posted Date

7-11-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20–0.66 μM). Resistance selection studies with ODV and GS-441524 against RSV identify a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated ~24 hours post-infection significantly reduces log10 viral RNA copies/mL × day area under the curve by 69–92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.

Keywords

Animals, Chlorocebus aethiops, Antiviral Agents, Respiratory Syncytial Virus Infections, Administration, Oral, Humans, Respiratory Syncytial Virus, Human, Drug Resistance, Viral, Female, Disease Models, Animal, Nucleosides, Adenosine, Antiviral agents, Pharmacodynamics

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.