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Remdesivir overcomes the S861 roadblock in SARS-CoV-2 polymerase elongation complex

ABSTRACT: Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID-19 treatment. However, the precise working mechanism of RDV when targeting the viral RNA-dependent RNA polymerase (RdRP) has not been fully elucidated. Here, we solve a 3.0-Å structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRP elongation complex (EC) and assess RDV intervention in polymerase elongation phase. Although RDV could induce an “i+3” delayed termination in meta-stable complexes, only pausing and subsequent elongation are observed in the EC. A comparative investigation using an enterovirus RdRP further confirms similar delayed intervention and demonstrates that steric hindrance of the RDV-characteristic 1′-cyano at the −4 position is responsible for the “i+3” intervention, although two representative Flaviviridae RdRPs do not exhibit similar behavior. A comparison of representative viral RdRP catalytic complex structures indicates that the product RNA backbone encounters highly conserved structural elements, highlighting the broad-spectrum intervention potential of 1′-modified nucleotide analogs in anti-RNA virus drug development. Graphical abstract Remdesivir (RDV), a drug effective in COVID-19 treatment, induces a characteristic delayed intervention once incorporated by the SARS-CoV-2 polymerase. Wu et al. reveal that RDV incorporated by SARS-CoV-2 polymerase elongation complex can pass the intervention site, while a similar mechanism is also found in enterovirus 71 polymerase.

SUBMITTER: Wu J

PROVIDER: S-EPMC8498683 | biostudies-literature |

REPOSITORIES: biostudies-literature

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