Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 and a variant of concern in ferrets (preprint)

Remdesivir is the only small-molecule antiviral approved to date for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterized the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibited SARS-CoV-2, including variants of concern (VoC) in cell culture. Oral GS-621763 was efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduced SARS-CoV-2 burden to near-undetectable levels. When dosed therapeutically against VoC P.1 gamma (γ), oral GS-621763 blocked virus replication and prevented transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.  

4'-Fluorouridine is a broad-spectrum orally efficacious antiviral blocking respiratory syncytial virus and SARS-CoV-2 replication (preprint)

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and the elderly. We describe 4'-fluorouridine (4'-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and SARS-CoV-2 with high selectivity index in cells and well-differentiated human airway epithelia. Polymerase inhibition in in vitro RdRP assays established for RSV and SARS-CoV-2 revealed transcriptional pauses at positions i or i+3/4 post-incorporation. Once-daily oral treatment was highly efficacious at 5 mg/kg in RSV-infected mice or 20 mg/kg in ferrets infected with SARS-CoV-2 WA1/2020 or variant-of-concern (VoC) isolate CA/2020, initiated 24 or 12 hours after infection, respectively. These properties define 4'-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2 and related RNA virus infections.

Therapeutic MK-4482/EIDD-2801 Blocks SARS-CoV-2 Transmission in Ferrets (preprint)

The COVID-19 pandemic is having a catastrophic impact on human health. Widespread community transmission has triggered stringent distancing measures with severe socioeconomic consequences. Gaining control of the pandemic will depend on interruption of transmission chains until protective herd immunity arises. Ferrets and related members of the weasel genus transmit SARS-CoV-2 efficiently with minimal clinical signs, resembling spread in the young-adult population. We previously reported an orally efficacious nucleoside analog inhibitor of influenza viruses, EIDD-2801 (or MK-4482), that was repurposed against SARS-CoV-2 and is in phase II/III clinical trials. Employing the ferret model, we demonstrate in this study high SARS-CoV-2 burden in nasal tissues and secretions that coincides with efficient direct-contact transmission. Therapeutic treatment of infected animals with twice-daily MK-4482/EIDD-2801 significantly reduced upper respiratory tract SARS-CoV-2 load and completely suppressed spread to untreated contact animals. This study identifies oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.