The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses
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.
Authors
- Michael L. Mallory (ORCID: https://orcid.org/0000-0003-0768-572X)
- Timothy P. Sheahan (ORCID: https://orcid.org/0000-0001-9181-2183)
- Richard L. Mackman (ORCID: https://orcid.org/0000-0001-8861-7205)
- Jason K. Perry (ORCID: https://orcid.org/0000-0001-5492-0652)
- Ralph Steven Baric (ORCID: https://orcid.org/0000-0001-6827-8701)
- Kendra L. Gully (ORCID: https://orcid.org/0000-0001-5742-2341)
- Joy Y. Feng (ORCID: https://orcid.org/0000-0003-4837-1911)
- Gabriela De la Cruz (ORCID: https://orcid.org/0000-0002-6019-5853)
- Nicholas J. Catanzaro
- Helen Conrad
- Darius Babusis (ORCID: https://orcid.org/0000-0001-5599-1671)
- Roy Bannister (ORCID: https://orcid.org/0000-0002-6311-1440)
- Stephanie Dong (ORCID: https://orcid.org/0000-0002-0318-5261)
- Tomáš Cihlář (ORCID: https://orcid.org/0000-0001-6840-0885)
- Fernando R. Moreira (ORCID: https://orcid.org/0000-0002-6606-7668)
- D. Trevor Scobey
- Boyd L. Yount (ORCID: https://orcid.org/0000-0002-6099-8429)
- Kimberly T. Barrett (ORCID: https://orcid.org/0000-0003-4128-8437)
- Samantha R. May
- Lily E. Adams (ORCID: https://orcid.org/0000-0001-7780-9973)
- John P. Bilello (ORCID: https://orcid.org/0000-0003-4327-1727)
- Mark R. Zweigart (ORCID: https://orcid.org/0000-0001-5765-3203)
- Anh-Quan Nguyen
- Meghan V. Diefenbacher (ORCID: https://orcid.org/0000-0002-8818-3686)
- Rao Kalla
- Thomas J Baric
- Anh‐Hoa Nguyen
- Cameron Nguyen (ORCID: https://orcid.org/0000-0003-2374-438X)
- Stephanie A Montgomery
- Ariane J. Brown
- David R. Martinez (ORCID: https://orcid.org/0000-0002-1689-5529)
- Alexandra Schäfer
Institutions
- University of North Carolina at Chapel Hill (US)
Publication Details
- Journal
- UNC Libraries
- Published
- 2024-10-03
- DOI
- https://doi.org/10.17615/ze7b-wm51
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- University of North Carolina at Chapel Hill
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases