Discovery of a non-nucleoside inhibitor that binds to a novel site in the palm domain of the respiratory syncytial virus RNA-dependent RNA polymerase.

ABSTRACT: Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract infections in infants, young children, and the elderly. We report herein the discovery and characterization of a novel RSV polymerase (RSVpol) non-nucleoside inhibitor (NNI) chemotype that binds to a previously undescribed, highly conserved site in the palm domain of the L protein. Consistent with the observed mode of inhibition, cryogenic electron microscopy (cryo-EM) revealed the site to be adjacent to the nucleotide binding site. Minireplicon assays confirmed on-target activity against RSVpol, and cell-based antiviral assays showed that the lead compound effectively inhibited viral mRNA transcription and replication in clinically relevant A and B strains. Together, our data provides valuable insights into the

SUBMITTER: Kalin JH 

PROVIDER: S-EPMC12282092 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature