RT Journal Article
SR Electronic
T1 Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.13.460111
DO 10.1101/2021.09.13.460111
A1 Alexandra Schäfer
A1 David R. Martinez
A1 John J. Won
A1 Fernando R. Moreira
A1 Ariane J. Brown
A1 Kendra L. Gully
A1 Rao Kalla
A1 Kwon Chun
A1 Venice Du Pont
A1 Darius Babusis
A1 Jennifer Tang
A1 Eisuke Murakami
A1 Raju Subramanian
A1 Kimberly T Barrett
A1 Blake J. Bleier
A1 Roy Bannister
A1 Joy Y. Feng
A1 John P. Bilello
A1 Tomas Cihlar
A1 Richard L. Mackman
A1 Stephanie A. Montgomery
A1 Ralph S. Baric
A1 Timothy P. Sheahan
YR 2021
UL http://biorxiv.org/content/early/2021/09/14/2021.09.13.460111.abstract
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 StatementThese authors are employees of Gilead Sciences and hold stock in Gilead Sciences: Rao Kalla, Kwon Chun, Venice Du Pont, Darius Babusis, Jennifer Tang, Eisuke Murakami, Raju Subramanian, Kimberly T Barrett, Blake J. Bleier, Roy Bannister, Joy Y. Feng, John P. Bilello, Tomas Cihlar, and Richard L. Mackman