tetano
Editor, Senior Moderator
Antimicrob Agents Chemother
. 2022 May 9;e0022222.
doi: 10.1128/aac.00222-22. Online ahead of print.
Remdesivir and GS-441524 Retain Antiviral Activity against Delta, Omicron, and Other Emergent SARS-CoV-2 Variants
Jared Pitts[SUP] 1 [/SUP], Jiani Li[SUP] 1 [/SUP], Jason K Perry[SUP] 1 [/SUP], Venice Du Pont[SUP] 1 [/SUP], Nicholas Riola[SUP] 1 [/SUP], Lauren Rodriguez[SUP] 1 [/SUP], Xianghan Lu[SUP] 1 [/SUP], Chaitanya Kurhade[SUP] 2 [/SUP], Xuping Xie[SUP] 2 [/SUP], Gregory Camus[SUP] 1 [/SUP], Savrina Manhas[SUP] 1 [/SUP], Ross Martin[SUP] 1 [/SUP], Pei-Yong Shi[SUP] 2 [/SUP], Tomas Cihlar[SUP] 1 [/SUP], Danielle P Porter[SUP] 1 [/SUP], Hongmei Mo[SUP] 1 [/SUP], Evguenia Maiorova[SUP] 1 [/SUP], John P Bilello[SUP] 1 [/SUP]
Affiliations
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[SUB]50[/SUB]) values 0.30- to 0.62-fold of those observed against the ancestral WA1 isolate. All other tested variants exhibited EC[SUB]50[/SUB] values ranging from 0.13- to 2.3-fold of the observed EC[SUB]50[/SUB] 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.
. 2022 May 9;e0022222.
doi: 10.1128/aac.00222-22. Online ahead of print.
Remdesivir and GS-441524 Retain Antiviral Activity against Delta, Omicron, and Other Emergent SARS-CoV-2 Variants
Jared Pitts[SUP] 1 [/SUP], Jiani Li[SUP] 1 [/SUP], Jason K Perry[SUP] 1 [/SUP], Venice Du Pont[SUP] 1 [/SUP], Nicholas Riola[SUP] 1 [/SUP], Lauren Rodriguez[SUP] 1 [/SUP], Xianghan Lu[SUP] 1 [/SUP], Chaitanya Kurhade[SUP] 2 [/SUP], Xuping Xie[SUP] 2 [/SUP], Gregory Camus[SUP] 1 [/SUP], Savrina Manhas[SUP] 1 [/SUP], Ross Martin[SUP] 1 [/SUP], Pei-Yong Shi[SUP] 2 [/SUP], Tomas Cihlar[SUP] 1 [/SUP], Danielle P Porter[SUP] 1 [/SUP], Hongmei Mo[SUP] 1 [/SUP], Evguenia Maiorova[SUP] 1 [/SUP], John P Bilello[SUP] 1 [/SUP]
Affiliations
- PMID: 35532238
- DOI: 10.1128/aac.00222-22
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[SUB]50[/SUB]) values 0.30- to 0.62-fold of those observed against the ancestral WA1 isolate. All other tested variants exhibited EC[SUB]50[/SUB] values ranging from 0.13- to 2.3-fold of the observed EC[SUB]50[/SUB] 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.