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<p>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 (EC<sub>50</sub>: 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 log<sub>10</sub> 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.</p>

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Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月11日

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  • Jared Pitts,
  • J. Lizbeth Reyes Zamora,
  • Savrina Manhas,
  • Thomas Aeschbacher,
  • Josolyn Chan,
  • Vincent Cutillas,
  • Varsha Nair,
  • Nicholas C. Riola,
  • Arya Vijjapurapu,
  • Meghan S. Vermillion,
  • Stacey Eng,
  • Christopher Richards,
  • Dong Han,
  • Jason K. Perry,
  • Subhra Chaudhuri,
  • Szu-Wen Liu,
  • Clarissa Martinez,
  • Nadine Peinovich,
  • Kai-Hui Sun,
  • Arthur Cai,
  • Ross Martin,
  • Jasmine Moshiri,
  • Charlotte Hedskog,
  • Darius Babusis,
  • Dustin S. Siegel,
  • Rao Kalla,
  • Vasanthi Avadhanula,
  • Pedro A. Piedra,
  • Kim Stobbelaar,
  • Peter L. Delputte,
  • Caleb Marceau,
  • Roberto Mateo,
  • Evguenia Maiorova,
  • Hongmei Mo,
  • Raju Subramanian,
  • Richard L. Mackman,
  • Tomas Cihlar,
  • Simon P. Fletcher,
  • John P. Bilello

摘要

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.