Highlights d Remdesivir binding of active site of polymerase is conserved across all human CoVs d Remdesivir inhibits SARS-CoV-2 in primary and continuous human lung cell cultures d Remdesivir potency depends on cell-type-specific metabolism to its active form d Therapeutic remdesivir reduces viral loads and improves outcomes in mice
A discovery program targeting respiratory
syncytial virus (RSV)
identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV
RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted
in the discovery of remdesivir (1, GS-5734) that is >30-fold
more potent than 4 against RSV in HEp-2 and NHBE cells.
Metabolism studies in vitro confirmed the rapid formation of the active
triphosphate metabolite, 1-NTP, and in vivo
studies in cynomolgus and African Green monkeys demonstrated a >10-fold
higher lung tissue concentration of 1-NTP following molar
normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an
African Green monkey RSV model demonstrated a >2-log10 reduction
in the peak lung viral load. These early data following the discovery
of 1 supported its potential as a novel treatment for
RSV prior to its development for Ebola and approval for COVID-19 treatment.
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. Additionally, 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 which 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.
1Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent 2 of the novel pandemic viral disease COVID-19. With no approved therapies, this pandemic illustrates the 3 urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging 4CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug of an adenosine analog, 5 potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial 6 cultures (EC50 = 0.01 µM). Weaker activity was observed in Vero E6 cells (EC50 = 1.65 µM) due to their 7 low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-8CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase, of SARS-CoV-2. In mice 9 infected with chimeric virus, therapeutic RDV administration diminished lung viral load and improved 10 pulmonary function as compared to vehicle treated animals. These data provide evidence that RDV is 11 potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for 12 treatment of COVID-19. 13 14 17 virus-specific (Sheahan et al., 2017). Together, these data demonstrate that RDV is potently antiviral 131 against SARS-CoV-2 in primary human lung cultures with a selectivity index of >1000. 132 Antiviral activities of RDV and GS-441524 correlate with RDV-TP metabolite levels. Cell type 133 specific expression of genes that metabolize ribonucleoside analogs can have a profound impact on 134 activity (Eriksson, 2013;Koczor et al., 2012). Table 1 and prior studies (Bojkova et al., 2020; Choy et al., 135 2020;Jeon et al., 2020) demonstrate the antiviral activity of RDV against SARS-CoV-2 is highly variable 136 in different cell culture models. Both RDV and GS-441524 undergo intracellular conversion to the active 137 metabolite RDV-TP involving several metabolic steps (Fig. S4) and the efficiency of each step might 138 differ between cell types. Therefore, to reconcile the differences in antiviral activity of RDV and GS-139 441524 observed in our and other studies, we compared intracellular RDV-TP concentrations in Vero E6, 140Calu3 2B4, and HAEs following incubation with the two compounds. RDV-TP levels per million cells
Genetic variation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence and rapid spread of multiple variants throughout the pandemic, of which Omicron is currently the predominant variant circulating worldwide. SARS-CoV-2 variants of concern/variants of interest (VOC/VOI) have evidence of increased viral transmission, disease severity, or decreased effectiveness of vaccines and neutralizing antibodies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.