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

Pitts, J.; Li, J.; Perry, J.; Du Pont, V.; Riola, N.; Rodriguez, L.; Lu, X.; Kurhade, C.; Xie, X.; Camus, G.; Manhas, S.; Martin, R.; Shi, P.-Y.; Cihlar, T.; Porter, D. P.; Mo, H.; Maiorova, E. S.; Bilello, J. P.

doi:10.1101/2022.02.09.479840

bioRxiv · 10.1101/2022.02.09.479840

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

Pitts, J.·Li, J.·Perry, J.·Du Pont, V.·Riola, N.·Rodriguez, L.·Lu, X.·Kurhade, C.·Xie, X.·Camus, G.·Manhas, S.·Martin, R.·Shi, P.-Y.·Cihlar, T.·Porter, D. P.·Mo, H.·Maiorova, E. S.·Bilello, J. P.

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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(R)) 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.

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Pitts, J., Li, J., Perry, J., Du Pont, V., Riola, N., Rodriguez, L., Lu, X., Kurhade, C., Xie, X., Camus, G., Manhas, S., Martin, R., Shi, P.-Y., Cihlar, T., Porter, D. P., Mo, H., Maiorova, E. S., Bilello, J. P.. 2022-02-10. Remdesivir and GS-441524 retain antiviral activity against Delta, Omicron, and other emergent SARS-CoV-2 variants. https://doi.org/10.1101/2022.02.09.479840

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