The
coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome coronavirus 2 (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. In addition, the emergence of SARS-CoV-2 variants of concern, with their potential to escape neutralization by 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 parent
nucleoside of
remdesivir, which targets the highly conserved virus RNA-dependent
RNA polymerase.
GS-621763 exhibited
antiviral activity against SARS-CoV-2 in lung cell lines and two different human primary lung cell culture systems.
GS-621763 was also potently
antiviral against a genetically unrelated emerging coronavirus,
Middle East respiratory syndrome CoV (MERS-CoV). 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 administration reduced viral load and lung pathology; treatment also improved pulmonary function in
COVID-19 mouse model. A direct comparison of
GS-621763 with
molnupiravir, an oral
nucleoside analog antiviral that has recently received EUA approval, proved both drugs to be similarly efficacious in mice. These data support the exploration of
GS-441524 oral
prodrugs for the treatment of
COVID-19.