2017 journal article

Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor.

Nature Communications.

MeSH headings : Animals; Animals, Newborn; Cell Line, Tumor; Chlorocebus aethiops; Epithelial Cells; Humans; Imidazolidines / metabolism; Imidazolidines / pharmacology; Imidazolidines / therapeutic use; Indoles / metabolism; Indoles / pharmacology; Indoles / therapeutic use; Molecular Structure; Pneumonia, Viral / drug therapy; Rats; Respiratory Mucosa / cytology; Respiratory Syncytial Virus Infections / drug therapy; Respiratory Syncytial Virus, Human / drug effects; Respiratory Syncytial Virus, Human / metabolism; Respiratory Syncytial Viruses / drug effects; Respiratory Syncytial Viruses / metabolism; Sheep; Structure-Activity Relationship; Vero Cells; Viral Fusion Protein Inhibitors / metabolism; Viral Fusion Protein Inhibitors / pharmacology; Viral Fusion Protein Inhibitors / therapeutic use; Viral Fusion Proteins / metabolism
Source: ORCID
Added: July 6, 2023

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.