{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T06:20:20Z","timestamp":1783750820660,"version":"3.55.0"},"reference-count":64,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"748","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,5,22]]},"abstract":"<jats:p>\n            Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV\u2013related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA\/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA\/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (M\n            <jats:sup>pro<\/jats:sup>\n            ) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adj4504","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T17:58:30Z","timestamp":1716400710000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":22,"title":["The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2940-8961","authenticated-orcid":true,"given":"David R.","family":"Martinez","sequence":"first","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA."},{"name":"Yale Center for Infection and Immunity, Yale School of Medicine, New Haven, CT 06510, 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Interim clinical considerations for COVID-19 treatment in outpatients (CDC 2024)."},{"key":"e_1_3_2_50_2","doi-asserted-by":"crossref","unstructured":"R. L. Mackman R. Kalla D. Babusis J. Pitts K. T. Barrett K. Chun V. D. Pont L. Rodriguez J. Moshiri Y. Xu M. Lee G. Lee B. Bleier A.-Q. Nguyen B. M. O\u2019Keefe A. Ambrosi M. Cook J. Yu E. Dempah E. Bunyan N. C. Riola X. Lu R. Liu A. Davie T.-Y. Hsiang M. Gale Jr A. Niedziela-Majka J. Y. Feng C. Hedskog J. P. Bilello R. Subramanian T. Cihlar Discovery of GS-5245 (obeldesivir) an oral prodrug of nucleoside GS-441524 that exhibits antiviral efficacy in SARS-CoV-2 infected African green monkeys. bioRxiv (2023); https:\/\/doi.org\/10.1101\/2023.04.28.538473.","DOI":"10.1101\/2023.04.28.538473"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009929"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199709113371101"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29104-y"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac769"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100735"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abq7360"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac496"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac512"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2282"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.24.15511-15524.2005"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.042"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1311542110"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.07.033"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2001046117"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000547"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adj4504","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T17:58:33Z","timestamp":1716400713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adj4504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,22]]},"references-count":64,"journal-issue":{"issue":"748","published-print":{"date-parts":[[2024,5,22]]}},"alternative-id":["10.1126\/scitranslmed.adj4504"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adj4504","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,22]]},"assertion":[{"value":"2023-06-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadj4504"}}