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Overcoming nonstructural protein 15-nidoviral uridylate-specific endoribonuclease (nsp15/NendoU) activity of SARS-CoV-2

ABSTRACT: COVID-19 has become the gravest global public health crisis since the Spanish Flu of 1918. Combination antiviral therapy with repurposed broad-spectrum antiviral agents holds a highly promising immediate treatment strategy, especially given uncertainties of vaccine efficacy and developmental timeline. Here, we describe a novel hypothetical approach: combining available broad-spectrum antiviral agents such as nucleoside analogs with potential inhibitors of NendoU, for example nsp15 RNA substrate mimetics. While only hypothesis-generating, this approach may constitute a ‘double-hit’ whereby two CoV-unique protein elements of the replicase–transcriptase complex are inhibited simultaneously; this may be an Achilles' heel and precipitate lethal mutagenesis in a coronavirus. It remains to be seen whether structurally optimized RNA substrate mimetics in combination with clinically approved and repurposed backbone antivirals can synergistically inhibit this endonuclease in vitro, thus fulfilling the ‘double-hit hypothesis’. Graphical abstract Replicase–transcriptase complex of SARS-CoV-2 & ‘double-hit hypothesis’ (Key: CoV-coronavirus, PLpro-Papain-like protease, 3CLpro-3CL protease, RdRp-RNA-dependent RNA polymerase, NendoU-endoribonuclease, ExoN exoribonuclease, 2′-O-Mtase-2′-O-ribose methyltransferase)

SUBMITTER: Senanayake S

PROVIDER: S-EPMC7255426 | biostudies-literature |

REPOSITORIES: biostudies-literature

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