Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor

Dirk Roymans (), Sarhad S Alnajjar, Michael B Battles, Panchan Sitthicharoenchai, Polina Furmanova-Hollenstein, Peter Rigaux, Joke Van den Berg, Leen Kwanten, Marcia Van Ginderen, Nick Verheyen, Luc Vranckx, Steffen Jaensch, Eric Arnoult, Richard Voorzaat, Jack M. Gallup, Alejandro Larios-Mora, Marjolein Crabbe, Dymphy Huntjens, Pierre Raboisson, Johannes P. Langedijk, Mark R. Ackermann, Jason S McLellan, Sandrine Vendeville and Anil Koul
Additional contact information
Dirk Roymans: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV
Sarhad S Alnajjar: College of Veterinary Medicine, Iowa State University
Michael B Battles: Geisel School of Medicine at Dartmouth
Panchan Sitthicharoenchai: College of Veterinary Medicine, Iowa State University
Polina Furmanova-Hollenstein: Janssen Vaccines and Prevention
Peter Rigaux: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV
Joke Van den Berg: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV
Leen Kwanten: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV
Marcia Van Ginderen: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV
Nick Verheyen: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV
Luc Vranckx: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV
Steffen Jaensch: Computational Biology, Janssen Pharmaceutica NV
Eric Arnoult: Computational Chemistry, Janssen R&D LLC
Richard Voorzaat: Janssen Vaccines and Prevention
Jack M. Gallup: College of Veterinary Medicine, Iowa State University
Alejandro Larios-Mora: College of Veterinary Medicine, Iowa State University
Marjolein Crabbe: Non-Clinical Statistics, Janssen Pharmaceutica NV
Dymphy Huntjens: Clinical Pharmacology and Pharmacometrics, Janssen Pharmaceutica NV
Pierre Raboisson: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV
Johannes P. Langedijk: Janssen Vaccines and Prevention
Mark R. Ackermann: College of Veterinary Medicine, Iowa State University
Jason S McLellan: Geisel School of Medicine at Dartmouth
Sandrine Vendeville: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV
Anil Koul: Janssen Infectious Diseases and Vaccines, Janssen Pharmaceutica NV

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00170-x

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