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TitleStructural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor.
Journal, issue, pagesCommun Biol, Vol. 6, Issue 1, Page 1074, Year 2023
Publish dateOct 21, 2023
AuthorsXiaodi Yu / Pravien Abeywickrema / Brecht Bonneux / Ishani Behera / Brandon Anson / Edgar Jacoby / Amy Fung / Suraj Adhikary / Anusarka Bhaumik / Rodrigo J Carbajo / Suzanne De Bruyn / Robyn Miller / Aaron Patrick / Quyen Pham / Madison Piassek / Nick Verheyen / Afzaal Shareef / Priscila Sutto-Ortiz / Nina Ysebaert / Herman Van Vlijmen / Tim H M Jonckers / Florence Herschke / Jason S McLellan / Etienne Decroly / Rachel Fearns / Sandrine Grosse / Dirk Roymans / Sujata Sharma / Peter Rigaux / Zhinan Jin /
PubMed AbstractThe respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA ...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.
External linksCommun Biol / PubMed:37865687 / PubMed Central
MethodsEM (single particle)
Resolution2.88 Å
Structure data

29452

8fu3

EMDB-29452, PDB-8fu3:
Structure Of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor
Method: EM (single particle) / Resolution: 2.88 Å

Chemicals

ChemComp-YBK:
8-methoxy-3-methyl-N-{(2S)-3,3,3-trifluoro-2-[5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-hydroxypropyl}cinnoline-6-carboxamide

Source
  • human respiratory syncytial virus a2
KeywordsVIRAL PROTEIN / RSV / Polymerase / Non-Nucleoside Inhibitor / TRANSFERASE

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