2. Academic Validation
  3. Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor

Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor

  • Nat Commun. 2017 Aug 1;8(1):167. doi: 10.1038/s41467-017-00170-x.
Dirk Roymans 1,  Sarhad S Alnajjar 2,  Michael B Battles 3,  Panchan Sitthicharoenchai 2,  Polina Furmanova-Hollenstein 4,  Peter Rigaux 5,  Joke Van den Berg 5,  Leen Kwanten 5,  Marcia Van Ginderen 5,  Nick Verheyen 5,  Luc Vranckx 5,  Steffen Jaensch 6,  Eric Arnoult 7,  Richard Voorzaat 4,  Jack M Gallup 2,  Alejandro Larios-Mora 2,  Marjolein Crabbe 8,  Dymphy Huntjens 9,  Pierre Raboisson 5,  Johannes P Langedijk 4,  Mark R Ackermann 2,  Jason S McLellan 3,  Sandrine Vendeville 5,  Anil Koul 5
Affiliations

Affiliations

  • 1 Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium. droymans@its.jnj.com.
  • 2 College of Veterinary Medicine, Iowa State University, 1800 Christensen Dr, Ames, IA, 50010, USA.
  • 3 Department of Biochemistry, Geisel School of Medicine at Dartmouth, 1 Rope Ferry Road, Hanover, NH, 03755, USA.
  • 4 Janssen Vaccines and Prevention, Newtonweg 1, 2333-CP, Leiden, The Netherlands.
  • 5 Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium.
  • 6 Computational Biology, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium.
  • 7 Computational Chemistry, Janssen R&D LLC, 1400 Mckean Road, Spring House, PA, 19477, USA.
  • 8 Non-Clinical Statistics, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium.
  • 9 Clinical Pharmacology and Pharmacometrics, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340, Beerse, Belgium.
PMID: 28761099 DOI: 10.1038/s41467-017-00170-x
Abstract

Respiratory syncytial virus is a major cause of acute lower respiratory tract Infection in young children, immunocompromised adults, and the elderly. Intervention with small-molecule antivirals specific for respiratory syncytial virus presents an important therapeutic opportunity, but no such compounds are approved today. Here we report the structure of JNJ-53718678 bound to respiratory syncytial virus fusion (F) protein in its prefusion conformation, and we show that the potent nanomolar activity of JNJ-53718678, as well as the preliminary structure-activity relationship and the pharmaceutical optimization strategy of the series, are consistent with the binding mode of JNJ-53718678 and other respiratory syncytial virus fusion inhibitors. Oral treatment of neonatal lambs with JNJ-53718678, or with an equally active close analog, efficiently inhibits established acute lower respiratory tract Infection in the Animals, even when treatment is delayed until external signs of respiratory syncytial virus illness have become visible. Together, these data suggest that JNJ-53718678 is a promising candidate for further development as a potential therapeutic in patients at risk to develop respiratory syncytial virus acute lower respiratory tract Infection.Respiratory syncytial virus causes lung infections in children, immunocompromised adults, and in the elderly. Here the authors show that a chemical inhibitor to a viral fusion protein is effective in reducing viral titre and ameliorating Infection in rodents and neonatal lambs.

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