Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor.

Respiratory Syncytial Virus, Human RNA-Dependent RNA Polymerase / chemistry Protein Binding RNA / metabolism Nucleotides / metabolism

Journal

Communications biology

ISSN: 2399-3642

Titre abrégé: Commun Biol

Pays: England

ID NLM: 101719179

Informations de publication

Date de publication:
21 10 2023

Historique:

received: 07 08 2023

accepted: 11 10 2023

medline: 31 10 2023

pubmed: 22 10 2023

entrez: 21 10 2023

Statut: epublish

Résumé

The respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA dependent RNA polymerase, capping, and Methyltransferase domains on L. Several nucleoside and non-nucleoside inhibitors have been reported to inhibit this polymerase complex, but the structural details of the exact inhibitor-polymerase interactions have been lacking. Here, we report a non-nucleoside inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral and polymerase assays. Our 2.9 Å resolution cryo-EM structure revealed that JNJ-8003 binds to an induced-fit pocket on the capping domain, with multiple interactions consistent with its tight binding and resistance mutation profile. The minigenome and gel-based de novo RNA synthesis and primer extension assays demonstrated that JNJ-8003 inhibited nucleotide polymerization at the early stages of RNA transcription and replication. Our results support that JNJ-8003 binding modulates a functional interplay between the capping and RdRp domains, and this molecular insight could accelerate the design of broad-spectrum antiviral drugs.

Identifiants

DOI: 10.1038/s42003-023-05451-4 PMID: 37865687 PMC: PMC10590419

pubmed: 37865687

doi: 10.1038/s42003-023-05451-4

pii: 10.1038/s42003-023-05451-4

pmc: PMC10590419

doi:

Substances chimiques

RNA-Dependent RNA Polymerase EC 2.7.7.48

RNA 63231-63-0

Nucleotides 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

1074

Informations de copyright

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