TitleTherapeutic efficacy of a respiratory syncytial virus fusion inhibitor.
Publication TypeJournal Article
Year of Publication2017
AuthorsRoymans, D, Alnajjar, SS, Battles, MB, Sitthicharoenchai, P, Furmanova-Hollenstein, P, Rigaux, P, Van den Berg, J, Kwanten, L, Van Ginderen, M, Verheyen, N, Vranckx, L, Jaensch, S, Arnoult, E, Voorzaat, R, Gallup, JM, Larios-Mora, A, Crabbe, M, Huntjens, D, Raboisson, P, Langedijk, JP, Ackermann, MR, McLellan, JS, Vendeville, S, Koul, A
JournalNat Commun
Date Published2017 08 01
KeywordsAnimals, Animals, Newborn, Cell Line, Tumor, Chlorocebus aethiops, Epithelial Cells, Humans, Imidazolidines, Indoles, Molecular Structure, Pneumonia, Viral, Rats, Respiratory Mucosa, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human, Respiratory Syncytial Viruses, Sheep, Structure-Activity Relationship, Vero Cells, Viral Fusion Protein Inhibitors, Viral Fusion Proteins

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.

Alternate JournalNat Commun
PubMed ID28761099
PubMed Central IDPMC5537225
Grant ListP20 GM113132 / GM / NIGMS NIH HHS / United States
T32 AI007519 / AI / NIAID NIH HHS / United States