Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice

Abstract

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.

The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants

“…S2A and B), probably due to the biostable amide group that obstructed hydrogen bond formation between the inhibitor and the RNA template ( 44 , 45 ). Tri-acetyl esterification of the hydroxyl groups on C5′ (R 1 ), C2’ (R 2 ) and C3′ (R 3 ) positions (ATV003) did not substantially change the activity, whereas the tri-isobutyryl on C5′ (R 1 ), C2’ (R 2 ) and C3′ (R 3 ) (ATV004), which has the same structure to GS-621763 ( 41 , 42 ), and mono-isobutyryl-modification of 5′-hydroxyl group (ATV006) improved the inhibitory activities in the replicon system in comparison with its parent GS-441524 (fig. S2B and table S1).…”

Remdesivir and GS-441524 Retain Antiviral Activity against Delta, Omicron, and Other Emergent SARS-CoV-2 Variants

“…As observed with RDV, GS-441524 maintained potency against all clinical isolates of variants tested, with a maximum fold change of 1.4 compared with WA1. Although the active triphosphates for GS-441524 and RDV are identical, it was important to confirm pan-variant GS-441524 potency because orally bioavailable prodrug options for delivery of GS-441524 are under exploration ( 43 , 44 ).…”

Molnupiravir combined with different repurposed drugs further inhibits SARS-CoV-2 infection in human nasal epithelium in vitro

“…In the current study, we assessed the antiviral potential of 99 single compounds at two study sites focusing on orally active drugs. Subsequently, we selected molnupiravir, an orally bioactive RdRp inhibitor recently approved by the American Food and Drug Administration (FDA), as a base compound for combination therapy [27] . We evaluated various concentrations of 30 drugs in combination with 10 µM molnupiravir against SARS-CoV-2 infection in reconstituted nasal epithelium.…”