학술논문
The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses.
Document Type
Academic Journal
Author
Martinez DR; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.; Yale Center for Infection and Immunity, Yale School of Medicine, New Haven, CT 06510, USA.; Moreira FR; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, 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; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.; Brown AJ; Department of Epidemiology, University of North Carolina at Chapel Hill, 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 Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.; Perry JK; Gilead Sciences, Inc., Foster City, CA 94404, 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; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.; Rapidly Emerging Antiviral Drug Development Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Mackman RL; Gilead Sciences, Inc., Foster City, CA 94404, USA.; Bilello JP; Gilead Sciences, Inc., Foster City, CA 94404, USA.; Schäfer A; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Rapidly Emerging Antiviral Drug Development Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Sheahan TP; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.; Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.; Rapidly Emerging Antiviral Drug Development Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Source
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
Subject
Language
English
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.