Mechanism of SARS-CoV-2 resistance to nucleotide analog-based antivirals.

ABSTRACT: The remarkable ability of SARS-CoV-2 to resist many nucleotide analog (NA)-based antivirals represents a formidable challenge to therapeutic efforts. Here, we reveal fundamental insights into how its unique proofreading exoribonuclease (ExoN) counteracts two representative NA antivirals, bemnifosbuvir and sofosbuvir, which are designed to inhibit the viral RNA polymerase (RdRp). Our findings unveil that NA incorporation alters RNA-binding dynamics, significantly increasing the affinity of RNA to ExoN while weakening its interaction with RdRp. This shift likely facilitates RNA dissociation from RdRp, subsequent recognition by ExoN, and excision of NAs. Strikingly, we elucidate the mechanism underlying varied levels of resilience of different NAs to ExoN excision. Our cryo-EM structures of E

SUBMITTER: Liu C 

PROVIDER: S-EPMC12905345 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature