Remdesivir and GS-441524 retain antiviral activity against Delta, Omicron, and other emergent SARS-CoV-2 variants

Abstract

Genetic variation of 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 or interest (VOC/VOI) have evidence of increased viral transmission, disease severity, or decreased effectiveness of vaccines and neutralizing antibodies. Remdesivir (RDV, VEKLURY®) is a nucleoside analog prodrug and the first FDA-approved antiviral treatment of COVID-19. Here we present a comprehensive antiviral activity assessment of RDV and its parent nucleoside, GS-441524, against 10 current and former SARS-CoV-2 VOC/VOI clinical isolates by nucleoprotein ELISA and plaque reduction assay. Delta and Omicron variants remained susceptible to RDV and GS-441524, with EC50 values 0.31 to 0.62-fold of those observed against the ancestral WA1 isolate. All other tested variants exhibited EC50 values ranging from 0.15 to 2.3-fold of the observed EC50 values against WA1. Analysis of nearly 6 million publicly available variant isolate sequences confirmed that Nsp12, the RNA-dependent RNA polymerase (RdRp) target of RDV and GS-441524, is highly conserved across variants with only 2 prevalent changes (P323L and G671S). Using recombinant viruses, both RDV and GS-441524 retained potency against all viruses containing frequent variant substitutions or their combination. Taken together, these results highlight the conserved nature of SARS-CoV-2 Nsp12 and provide evidence of sustained SARS-CoV-2 antiviral activity of RDV and GS-441524 across the tested variants. The observed pan-variant activity of RDV supports its continued use for the treatment of COVID-19 regardless of the SARS-CoV-2 variant.

Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infection

“…RDV (VEKLURY®) was the first approved therapy for patients with COVID-19 in the United States, Japan, the European Union, and other countries. Both RDV and its parent nucleoside, GS-441524, retain in vitro potency across all recently emergent variants of concern and variants of interest ( Pitts et al, 2022 ). In addition to SARS-CoV-2 antiviral activity, RDV has previously demonstrated potent activity against other epidemic coronaviruses, such as SARS-CoV and MERS-CoV ( Sheahan et al, 2017 , 2020 ; Agostini et al, 2018 ).…”

In Vitro Selection of Remdesivir-Resistant SARS-CoV-2 Demonstrates High Barrier to Resistance

“…The reverse genetics system was kindly provided by the University of Texas Medical Branch (Galveston, TX), and the procedures required to assemble and produce SARS-CoV-2 infectious strains have been previously described in detail by Xie et al ( 12 ). Antiviral activity (EC 50 value) of RDV against SARS-CoV-2-Nluc was evaluated with a luciferase assay as reported ( 13 ) with some modifications ( 14 ).…”

“…Supernatants were harvested at times 0, 8, 24, 48, 72, and 96 h postinfection. Titers were determined for each time point by plaque assay ( 14 ). The data represent three individual experiments for each time point for each recombinant virus.…”

Journey of remdesivir from the inhibition of hepatitis C virus to the treatment of COVID-19

“…In contrast, the RdRp gene (nsp12) of the newly emerged SARS-CoV-2 variants remains genetically stable with only a few mutations located further away from the enzyme active site. Consistent with this observation, RDV retains its full antiviral activity against all major variants of concern including Delta and Omicron [80, 81, 82].…”