PT  - JOURNAL ARTICLE
AU  - Alexandra Schäfer
AU  - David R. Martinez
AU  - John J. Won
AU  - Fernando R. Moreira
AU  - Ariane J. Brown
AU  - Kendra L. Gully
AU  - Rao Kalla
AU  - Kwon Chun
AU  - Venice Du Pont
AU  - Darius Babusis
AU  - Jennifer Tang
AU  - Eisuke Murakami
AU  - Raju Subramanian
AU  - Kimberly T Barrett
AU  - Blake J. Bleier
AU  - Roy Bannister
AU  - Joy Y. Feng
AU  - John P. Bilello
AU  - Tomas Cihlar
AU  - Richard L. Mackman
AU  - Stephanie A. Montgomery
AU  - Ralph S. Baric
AU  - Timothy P. Sheahan
TI  - Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice
AID  - 10.1101/2021.09.13.460111
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.09.13.460111
4099  - http://biorxiv.org/content/early/2021/09/13/2021.09.13.460111.short
4100  - http://biorxiv.org/content/early/2021/09/13/2021.09.13.460111.full
AB  - The COVID-19 pandemic remains uncontrolled despite the rapid rollout of safe and effective SARS-CoV-2 vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern with their potential to escape therapeutic monoclonal antibodies emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parental nucleoside of remdesivir, which targets the highly conserved RNA-dependent RNA polymerase. GS-621763 exhibited significant antiviral activity in lung cell lines and two different human primary lung cell culture systems. The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 significantly reduced viral load, lung pathology, and improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral currently in human clinical trial, proved both drugs to be similarly efficacious. These data demonstrate that therapy with oral prodrugs of remdesivir can significantly improve outcomes in SARS-CoV-2 infected mice. Thus, GS-621763 should be explored as a potential treatment for COVID-19 in humans.Competing Interest StatementThe authors have declared no competing interest.