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JAC Advance Access published online on January 28, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh558
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JAC © The British Society for Antimicrobial Chemotherapy 2005; all rights reserved

Original article

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

Christopher Cianci 1, Nicholas Meanwell 2, and Mark Krystal 1*

1 Departments of Virology and, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
2 Department ofChemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA

* To whom correspondence should be addressed.
Mark Krystal, E-mail: Mark.Krystal{at}bms.com


  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 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.

Keywords: respiratory syncytial virus; trimer-of-hairpins; heptad repeats; BMS-433771.
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