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

[tetano]

Cell Rep


. 2021 Oct 8;109882.
doi: 10.1016/j.celrep.2021.109882. Online ahead of print.
Remdesivir overcomes the S861 roadblock in SARS-CoV-2 polymerase elongation complex


Jiqin Wu ¹ , Haofeng Wang ² , Qiaojie Liu ¹ , Rui Li ³ , Yan Gao ⁴ , Xiang Fang ³ , Yao Zhong ³ , Meihua Wang ³ , Quan Wang ⁵ , Zihe Rao ⁶ , Peng Gong ⁷



Affiliations

• PMID: 34653416
• DOI: 10.1016/j.celrep.2021.109882

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.

Keywords: RNA-dependent RNA polymerase; SARS-CoV-2; broad-spectrum; elongation complex; remdesivir.