Antiviral activity and molecular mechanism of an orally active respiratory syncytial virus fusion inhibitor.
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.
Cianci
Christopher
C
Department of Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
Meanwell
Nicholas
N
Krystal
Mark
M
D000284:Administration, Oral; D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*
D000998:Antiviral Agents; C482453:BMS 433771; D001562:Benzimidazoles