Abstract
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. 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 enzyme-linked immunosorbent assay (ELISA) and plaque reduction assay. Delta and Omicron variants remained susceptible to RDV and GS-441524, with 50% effective concentration (EC 50 ) values 0.30- to 0.62-fold of those observed against the ancestral WA1 isolate. All other tested variants exhibited EC 50 values ranging from 0.13- to 2.3-fold of the observed EC 50 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.
Keywords: COVID-19; GS-441524; Nsp12; SARS-CoV-2 variants; antiviral agents; remdesivir.
【저자키워드】 COVID-19, Nsp12, Remdesivir, SARS-CoV-2 variants, Antiviral agents, GS-441524, 【초록키워드】 Treatment, viruses, SARS-CoV-2, Vaccine, coronavirus, pandemic, Nsp12, Antiviral, Neutralizing antibodies, disease severity, Variation, variant, SARS-CoV-2 variant, Delta, Remdesivir, Antiviral treatment, antiviral activity, severe acute respiratory syndrome Coronavirus, omicron, virus, Omicron variants, variants, ELISA, Spread, enzyme-linked immunosorbent assay, SARS-CoV-2 variants, Genetic variation, Antiviral agents, GS-441524, Effectiveness, RdRP, RNA-dependent RNA polymerase, Viral transmission, change, RDV, Evidence, Combination, evidence of, Support, reduction, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, sequences, P323L, sequence, potency, nucleoside, Substitution, fold, circulating, Veklury, parent nucleoside, 50% effective concentration, isolate, susceptible, prevalent, enzyme-linked immunosorbent, highlight, tested, conserved, remained, exhibited, predominant, retained, sustained, the SARS-CoV-2, WA1, 【제목키워드】 SARS-CoV-2, Delta, activity, Other,