Antiviral activity and molecular mechanism of an orally active respiratory syncytial virus fusion inhibitor

• Published in: Journal of antimicrobial chemotherapy 2005-03, Vol.55 (3), p.289-292
• Main Authors: Cianci, Christopher, Meanwell, Nicholas, Krystal, Mark
• Format: Article
• Language: English
• Subjects: Administration, Oral; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral Agents - pharmacology; Benzimidazoles - pharmacology; Biological and medical sciences; BMS-433771; heptad repeats; Human immunodeficiency virus; Humans; Medical sciences; Membrane Fusion - drug effects; Pharmacology. Drug treatments; Respiratory syncytial virus; Respiratory Syncytial Viruses - drug effects; trimer-of-hairpins
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkh558

BMS-433771 is an orally bioavailable respiratory syncytial virus (RSV) inhibitor, functioning through inhibition of viral F protein-induced membrane fusion. The compound is active against both A and B groups of RSV, with an average EC50 of 20 nM. BMS-433771 is also efficacious against RSV infection in two rodent models when dosed orally prior to infection. The compound possesses good pharmacokinetic properties, while maintaining a favourable toxicity profile. Consequently, BMS-433771 is well suited for further clinical evaluation in humans. Direct affinity labelling studies indicate that the compound binds in a hydrophobic cavity within the trimeric N-terminal heptad repeat. During the fusion process, this heptad repeat associates with a C-terminal heptad repeat to form a six helical coiled-coil bundle (or trimer-of-hairpins), and BMS-433771 presumably interferes with the functional association of these heptad repeats. The fusion protein of many other class 1 fusion viruses, such as HIV and influenza, form similar hairpin structures as a prelude to membrane fusion. The identification of BMS-433771 provides a proof of concept for small molecule inhibitors that target the formation of the six helical coiled-coil structure, which could be a prototype for the development of similar antivirals against other class 1 fusion viruses.