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Journal Articles Communications Biology Year : 2023

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

Xiaodi Yu
Pravien Abeywickrema
  • Function : Author
Brecht Bonneux
Ishani Behera
  • Function : Author
Brandon Anson
  • Function : Author
Edgar Jacoby
  • Function : Author
Amy Fung
  • Function : Author
Suraj Adhikary
  • Function : Author
Anusarka Bhaumik
  • Function : Author
Rodrigo Carbajo
Suzanne de Bruyn
Robyn Miller
  • Function : Author
Aaron Patrick
  • Function : Author
Quyen Pham
  • Function : Author
Madison Piassek
  • Function : Author
Nick Verheyen
  • Function : Author
Afzaal Shareef
Priscila Sutto-Ortiz
  • Function : Author
Nina Ysebaert
  • Function : Author
Herman van Vlijmen
  • Function : Author
Tim Jonckers
  • Function : Author
Florence Herschke
  • Function : Author
Jason Mclellan
Rachel Fearns
Sandrine Grosse
  • Function : Author
Dirk Roymans
  • Function : Author
Sujata Sharma
  • Function : Author
Peter Rigaux
  • Function : Author
Zhinan Jin

Abstract

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.
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hal-04260207 , version 1 (26-10-2023)

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Xiaodi Yu, Pravien Abeywickrema, Brecht Bonneux, Ishani Behera, Brandon Anson, et al.. Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor. Communications Biology, 2023, 6 (1), pp.1074. ⟨10.1038/s42003-023-05451-4⟩. ⟨hal-04260207⟩
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