Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys
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...
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2025-07-01
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| Online Access: | https://doi.org/10.1038/s41467-025-61595-3 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jared Pitts |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e0dcb535da4e492b9e62e40a3babbfcf |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-e0dcb535da4e492b9e62e40a3babbfcf2025-08-20T03:43:22ZengNature PortfolioNature Communications2041-17232025-07-0116111210.1038/s41467-025-61595-3Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeysJared Pitts0J. Lizbeth Reyes Zamora1Savrina Manhas2Thomas Aeschbacher3Josolyn Chan4Vincent Cutillas5Varsha Nair6Nicholas C. Riola7Arya Vijjapurapu8Meghan S. Vermillion9Stacey Eng10Christopher Richards11Dong Han12Jason K. Perry13Subhra Chaudhuri14Szu-Wen Liu15Clarissa Martinez16Nadine Peinovich17Kai-Hui Sun18Arthur Cai19Ross Martin20Jasmine Moshiri21Charlotte Hedskog22Darius Babusis23Dustin S. Siegel24Rao Kalla25Vasanthi Avadhanula26Pedro A. Piedra27Kim Stobbelaar28Peter L. Delputte29Caleb Marceau30Roberto Mateo31Evguenia Maiorova32Hongmei Mo33Raju Subramanian34Richard L. Mackman35Tomas Cihlar36Simon P. Fletcher37John P. Bilello38Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Lovelace Biomedical Research InstituteGilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Molecular Virology and Microbiology, Baylor College of MedicineMolecular Virology and Microbiology, Baylor College of MedicineLaboratory for Microbiology, Parasitology and Hygiene (LMPH), University of AntwerpLaboratory for Microbiology, Parasitology and Hygiene (LMPH), University of AntwerpGilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.Gilead Sciences, Inc.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.https://doi.org/10.1038/s41467-025-61595-3 |
| spellingShingle | 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 Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys Nature Communications |
| title | Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys |
| title_full | Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys |
| title_fullStr | Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys |
| title_full_unstemmed | Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys |
| title_short | Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys |
| title_sort | oral dosing of the nucleoside analog obeldesivir is efficacious against rsv infection in african green monkeys |
| url | https://doi.org/10.1038/s41467-025-61595-3 |
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