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The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses.
Martinez, David R; Moreira, Fernando R; Catanzaro, Nicholas J; Diefenbacher, Meghan V; Zweigart, Mark R; Gully, Kendra L; De la Cruz, Gabriela; Brown, Ariane J; Adams, Lily E; Yount, Boyd; Baric, Thomas J; Mallory, Michael L; Conrad, Helen; May, Samantha R; Dong, Stephanie; Scobey, D Trevor; Nguyen, Cameron; Montgomery, Stephanie A; Perry, Jason K; Babusis, Darius; Barrett, Kimberly T; Nguyen, Anh-Hoa; Nguyen, Anh-Quan; Kalla, Rao; Bannister, Roy; Feng, Joy Y; Cihlar, Tomas; Baric, Ralph S; Mackman, Richard L; Bilello, John P; Schäfer, Alexandra; Sheahan, Timothy P.
Afiliación
  • Martinez DR; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.
  • Moreira FR; Yale Center for Infection and Immunity, Yale School of Medicine, New Haven, CT 06510, USA.
  • Catanzaro NJ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Diefenbacher MV; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Zweigart MR; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Gully KL; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • De la Cruz G; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Brown AJ; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • Adams LE; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Yount B; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Baric TJ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Mallory ML; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Conrad H; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • May SR; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Dong S; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Scobey DT; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Nguyen C; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Montgomery SA; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Perry JK; Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • Babusis D; Gilead Sciences, Inc., Foster City, CA 94404, USA.
  • Barrett KT; Gilead Sciences, Inc., Foster City, CA 94404, USA.
  • Nguyen AH; Gilead Sciences, Inc., Foster City, CA 94404, USA.
  • Nguyen AQ; Gilead Sciences, Inc., Foster City, CA 94404, USA.
  • Kalla R; Gilead Sciences, Inc., Foster City, CA 94404, USA.
  • Bannister R; Gilead Sciences, Inc., Foster City, CA 94404, USA.
  • Feng JY; Gilead Sciences, Inc., Foster City, CA 94404, USA.
  • Cihlar T; Gilead Sciences, Inc., Foster City, CA 94404, USA.
  • Baric RS; Gilead Sciences, Inc., Foster City, CA 94404, USA.
  • Mackman RL; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Bilello JP; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • Schäfer A; Rapidly Emerging Antiviral Drug Development Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Sheahan TP; Gilead Sciences, Inc., Foster City, CA 94404, USA.
Sci Transl Med ; 16(748): eadj4504, 2024 May 22.
Article en En | MEDLINE | ID: mdl-38776389
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 (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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Profármacos / SARS-CoV-2 Límite: Animals / Female / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Profármacos / SARS-CoV-2 Límite: Animals / Female / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos