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

Jared Pitts, Jiani Li, Jason K. Perry, Venice Du Pont, Nicholas Riola, Lauren Rodriguez, Xianghan Lu, Chaitanya Kurhade, Xuping Xie, Gregory Camus, Savrina Manhas, Ross Martin, Pei Yong Shi, Tomas Cihlar, Danielle P. Porter, Hongmei Mo, Evguenia Maiorova, John P. Bilello

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Genetic variation of severe acute respiratory syndrome coronavirus 2 (SARSCoV- 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 (EC50) values 0.30- to 0.62-fold of those observed against the ancestral WA1 isolate. All other tested variants exhibited EC50 values ranging from 0.13- 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.

Original languageEnglish (US)
JournalAntimicrobial agents and chemotherapy
Volume66
Issue number6
DOIs
StatePublished - Jun 2022

Keywords

  • COVID-19
  • GS-441524
  • Nsp12
  • SARS-CoV-2 variants
  • antiviral agents
  • remdesivir

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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