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Sci Transl Med
. 2024 May 22;16(748):eadj4504.
doi: 10.1126/scitranslmed.adj4504. Epub 2024 May 22. The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses
David R Martinez 1 2 , Fernando R Moreira 3 , Nicholas J Catanzaro 3 , Meghan V Diefenbacher 3 , Mark R Zweigart 3 , Kendra L Gully 3 , Gabriela De la Cruz 4 , Ariane J Brown 3 , Lily E Adams 3 , Boyd Yount 3 , Thomas J Baric 3 , Michael L Mallory 3 , Helen Conrad 3 , Samantha R May 3 , Stephanie Dong 3 , D Trevor Scobey 3 , Cameron Nguyen 3 , Stephanie A Montgomery 5 , Jason K Perry 6 , Darius Babusis 6 , Kimberly T Barrett 6 , Anh-Hoa Nguyen 6 , Anh-Quan Nguyen 6 , Rao Kalla 6 , Roy Bannister 6 , Joy Y Feng 6 , Tomas Cihlar 6 , Ralph S Baric 3 7 8 , Richard L Mackman 6 , John P Bilello 6 , Alexandra Schäfer 3 8 , Timothy P Sheahan 3 7 8
Affiliations
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-related 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 (Mpro) 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.
. 2024 May 22;16(748):eadj4504.
doi: 10.1126/scitranslmed.adj4504. Epub 2024 May 22. The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses
David R Martinez 1 2 , Fernando R Moreira 3 , Nicholas J Catanzaro 3 , Meghan V Diefenbacher 3 , Mark R Zweigart 3 , Kendra L Gully 3 , Gabriela De la Cruz 4 , Ariane J Brown 3 , Lily E Adams 3 , Boyd Yount 3 , Thomas J Baric 3 , Michael L Mallory 3 , Helen Conrad 3 , Samantha R May 3 , Stephanie Dong 3 , D Trevor Scobey 3 , Cameron Nguyen 3 , Stephanie A Montgomery 5 , Jason K Perry 6 , Darius Babusis 6 , Kimberly T Barrett 6 , Anh-Hoa Nguyen 6 , Anh-Quan Nguyen 6 , Rao Kalla 6 , Roy Bannister 6 , Joy Y Feng 6 , Tomas Cihlar 6 , Ralph S Baric 3 7 8 , Richard L Mackman 6 , John P Bilello 6 , Alexandra Schäfer 3 8 , Timothy P Sheahan 3 7 8
Affiliations
- PMID: 38776389
- DOI: 10.1126/scitranslmed.adj4504
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-related 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 (Mpro) 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.