Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor
| Autor: | Sarhad Alnajjar, Alejandro Larios-Mora, Marjolein Crabbe, Dymphy Huntjens, Eric Arnoult, Nick Verheyen, Jason S. McLellan, Mark R. Ackermann, Jack M. Gallup, Anil Koul, Leen Kwanten, Michael B. Battles, Steffen Jaensch, Joke Van den Berg, Luc Vranckx, Marcia Van Ginderen, Dirk Roymans, Panchan Sitthicharoenchai, Richard Voorzaat, Peter Rigaux, Sandrine Vendeville, Pierre Jean-Marie Bernard Raboisson, Polina Furmanova-Hollenstein, Johannes P. M. Langedijk |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Indoles viruses Science Fusion inhibitor Pneumonia Viral General Physics and Astronomy Respiratory Mucosa Respiratory Syncytial Virus Infections Biology Imidazolidines General Biochemistry Genetics and Molecular Biology Virus Article 03 medical and health sciences Structure-Activity Relationship Cell Line Tumor Chlorocebus aethiops medicine Animals Humans Respiratory system Vero Cells Viral Fusion Protein Inhibitors Multidisciplinary Lung Sheep Molecular Structure Epithelial Cells General Chemistry respiratory system medicine.disease Fusion protein Virology Rats Respiratory Syncytial Viruses Pneumonia 030104 developmental biology medicine.anatomical_structure Animals Newborn Respiratory Syncytial Virus Human Immunology Vero cell Viral load Viral Fusion Proteins |
| Zdroj: | Nature Communications Nature Communications, Vol 8, Iss 1, Pp 1-15 (2017) |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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