5KWW

Crystal Structure of Inhibitor JNJ-53718678 In Complex with Prefusion RSV F Glycoprotein

Summary for 5KWW

• Entry DOI: 10.2210/pdb5kww/pdb
• Descriptor: Fusion glycoprotein F0, Envelope glycoprotein chimera, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID, ... (6 entities in total)
• Functional Keywords: class i viral fusion protein, respiratory syncytial virus, viral protein, fusion inhibitor, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Human respiratory syncytial virus; More
• Total number of polymer chains: 1
• Total formula weight: 65108.39

Authors

McLellan, J.S.,Battles, M.B.,Arnoult, E.,Roymans, D.,Langedijk, J.P. (deposition date: 2016-07-19, release date: 2017-08-02, Last modification date: 2024-10-16)

Primary citation

Roymans, D.,Alnajjar, S.S.,Battles, M.B.,Sitthicharoenchai, P.,Furmanova-Hollenstein, P.,Rigaux, P.,Berg, J.V.D.,Kwanten, L.,Ginderen, M.V.,Verheyen, N.,Vranckx, L.,Jaensch, S.,Arnoult, E.,Voorzaat, R.,Gallup, J.M.,Larios-Mora, A.,Crabbe, M.,Huntjens, D.,Raboisson, P.,Langedijk, J.P.,Ackermann, M.R.,McLellan, J.S.,Vendeville, S.,Koul, A.
Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor.
Nat Commun, 8:167-167, 2017

PubMed 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.

PubMed: 28761099
DOI: 10.1038/s41467-017-00170-x

Experimental method

X-RAY DIFFRACTION (2.5 Å)