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

Abstract

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 EC(50) 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.

• Authors: Christopher Cianci, Nicholas Meanwell, Mark Krystal
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 55 Issue 3 Pg. 289-92 (Mar 2005) ISSN: 0305-7453 [Print] England
• PMID: 15681582 (Publication Type: Journal Article, Review)

Chemical References

• Antiviral Agents
• BMS 433771
• Benzimidazoles

Topics

• Administration, Oral
• Antiviral Agents (pharmacology)
• Benzimidazoles (pharmacology)
• Humans
• Membrane Fusion (drug effects)
• Respiratory Syncytial Viruses (drug effects)