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

Remdesivir (RDV), a nucleotide analog with broad-spectrum features, has exhibited effectiveness in COVID19 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-A 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+3delayed 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+3intervention, 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 10-modified nucleotide analogs in anti-RNA virus drug development.

Automated summary

Remdesivir, a nucleotide analog, has shown effectiveness in treating COVID19, but its precise working mechanism targeting viral RNA-dependent RNA polymerase is not fully elucidated. This study provides insights into RDV intervention in polymerase elongation phase and highlights the potential of modified nucleotide analogs in developing broad-spectrum anti-RNA virus drugs.