tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Fernando R Moreira[SUP] 3 [/SUP], Nicholas J Catanzaro[SUP] 3 [/SUP], Meghan V Diefenbacher[SUP] 3 [/SUP], Mark R Zweigart[SUP] 3 [/SUP], Kendra L Gully[SUP] 3 [/SUP], Gabriela De la Cruz[SUP] 4 [/SUP], Ariane J Brown[SUP] 3 [/SUP], Lily E Adams[SUP] 3 [/SUP], Boyd Yount[SUP] 3 [/SUP], Thomas J Baric[SUP] 3 [/SUP], Michael L Mallory[SUP] 3 [/SUP], Helen Conrad[SUP] 3 [/SUP], Samantha R May[SUP] 3 [/SUP], Stephanie Dong[SUP] 3 [/SUP], D Trevor Scobey[SUP] 3 [/SUP], Cameron Nguyen[SUP] 3 [/SUP], Stephanie A Montgomery[SUP] 5 [/SUP], Jason K Perry[SUP] 6 [/SUP], Darius Babusis[SUP] 6 [/SUP], Kimberly T Barrett[SUP] 6 [/SUP], Anh-Hoa Nguyen[SUP] 6 [/SUP], Anh-Quan Nguyen[SUP] 6 [/SUP], Rao Kalla[SUP] 6 [/SUP], Roy Bannister[SUP] 6 [/SUP], Joy Y Feng[SUP] 6 [/SUP], Tomas Cihlar[SUP] 6 [/SUP], Ralph S Baric[SUP] 3 7 8 [/SUP], Richard L Mackman[SUP] 6 [/SUP], John P Bilello[SUP] 6 [/SUP], Alexandra Schäfer[SUP] 3 8 [/SUP], Timothy P Sheahan[SUP] 3 7 8 [/SUP]
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 (M[SUP]pro[/SUP]) 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[SUP] 1 2 [/SUP], Fernando R Moreira[SUP] 3 [/SUP], Nicholas J Catanzaro[SUP] 3 [/SUP], Meghan V Diefenbacher[SUP] 3 [/SUP], Mark R Zweigart[SUP] 3 [/SUP], Kendra L Gully[SUP] 3 [/SUP], Gabriela De la Cruz[SUP] 4 [/SUP], Ariane J Brown[SUP] 3 [/SUP], Lily E Adams[SUP] 3 [/SUP], Boyd Yount[SUP] 3 [/SUP], Thomas J Baric[SUP] 3 [/SUP], Michael L Mallory[SUP] 3 [/SUP], Helen Conrad[SUP] 3 [/SUP], Samantha R May[SUP] 3 [/SUP], Stephanie Dong[SUP] 3 [/SUP], D Trevor Scobey[SUP] 3 [/SUP], Cameron Nguyen[SUP] 3 [/SUP], Stephanie A Montgomery[SUP] 5 [/SUP], Jason K Perry[SUP] 6 [/SUP], Darius Babusis[SUP] 6 [/SUP], Kimberly T Barrett[SUP] 6 [/SUP], Anh-Hoa Nguyen[SUP] 6 [/SUP], Anh-Quan Nguyen[SUP] 6 [/SUP], Rao Kalla[SUP] 6 [/SUP], Roy Bannister[SUP] 6 [/SUP], Joy Y Feng[SUP] 6 [/SUP], Tomas Cihlar[SUP] 6 [/SUP], Ralph S Baric[SUP] 3 7 8 [/SUP], Richard L Mackman[SUP] 6 [/SUP], John P Bilello[SUP] 6 [/SUP], Alexandra Schäfer[SUP] 3 8 [/SUP], Timothy P Sheahan[SUP] 3 7 8 [/SUP]
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 (M[SUP]pro[/SUP]) 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.