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

Autor: Yu X; Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania, PA, 19477, USA. xyu6@its.jnj.com., Abeywickrema P; Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania, PA, 19477, USA., Bonneux B; Janssen Infectious Diseases and Vaccines, 2340, Beerse, Belgium.; University of Antwerp, Antwerp, Belgium., Behera I; Johnson & Johnson Innovative Medicine, Brisbane, CA, 94005, USA., Anson B; Johnson & Johnson Innovative Medicine, Brisbane, CA, 94005, USA., Jacoby E; Johnson & Johnson Innovative Medicine, Beerse, Belgium., Fung A; Johnson & Johnson Innovative Medicine, Brisbane, CA, 94005, USA., Adhikary S; Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania, PA, 19477, USA., Bhaumik A; Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania, PA, 19477, USA., Carbajo RJ; Johnson & Johnson Innovative Medicine, Janssen-Cilag, Discovery Chemistry S.A. Río Jarama, 75A, 45007, Toledo, Spain., De Bruyn S; Janssen Infectious Diseases and Vaccines, 2340, Beerse, Belgium., Miller R; Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania, PA, 19477, USA., Patrick A; Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania, PA, 19477, USA., Pham Q; Johnson & Johnson Innovative Medicine, Brisbane, CA, 94005, USA., Piassek M; Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania, PA, 19477, USA., Verheyen N; Janssen Infectious Diseases and Vaccines, 2340, Beerse, Belgium., Shareef A; Department of Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA., Sutto-Ortiz P; Aix Marseille Université, CNRS, AFMB, UMR 7257, Marseille, France., Ysebaert N; Janssen Infectious Diseases and Vaccines, 2340, Beerse, Belgium., Van Vlijmen H; Johnson & Johnson Innovative Medicine, Beerse, Belgium., Jonckers THM; Johnson & Johnson Innovative Medicine, Beerse, Belgium., Herschke F; Janssen Infectious Diseases and Vaccines, 2340, Beerse, Belgium., McLellan JS; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA., Decroly E; Aix Marseille Université, CNRS, AFMB, UMR 7257, Marseille, France., Fearns R; Department of Microbiology, National Emerging Infectious Diseases Laboratories, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA., Grosse S; Johnson & Johnson Innovative Medicine, Beerse, Belgium., Roymans D; Janssen Infectious Diseases and Vaccines, 2340, Beerse, Belgium., Sharma S; Johnson & Johnson Innovative Medicine, Spring House, Pennsylvania, PA, 19477, USA., Rigaux P; Janssen Infectious Diseases and Vaccines, 2340, Beerse, Belgium., Jin Z; Johnson & Johnson Innovative Medicine, Brisbane, CA, 94005, USA. zjin14@its.jnj.com.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Oct 21; Vol. 6 (1), pp. 1074. Date of Electronic Publication: 2023 Oct 21.
DOI: 10.1038/s42003-023-05451-4
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje