The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses
David R. Martinez, Fernando R. Moreira, Nicholas Catanzaro, Meghan V. Diefenbacher, Mark R. Zweigart, Kendra L. Gully, Gabriela De la Cruz, Ariane J. Brown, Lily E. Adams, Boyd L. Yount, Thomas J. Baric, Michael L. Mallory, Helen Conrad, Samantha R. May, Stephanie Dong, D. Trevor Scobey, Cameron Nguyen, Stephanie A. Montgomery, Jason K. Perry, Darius Babusis, Kimberly T. Barrett, Anh‐Hoa Nguyen, Anh-Quan Nguyen, Rao Kalla, Roy Bannister, Joy Y. Feng, Tomáš Cihlář, Ralph S. Baric, Richard L. Mackman, John P. Bilello, Alexandra Schäfer, Timothy P. Sheahan
Abstract
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 pro ) 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.