Journal Article

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

Christopher Cianci, Nicholas Meanwell and Mark Krystal

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 55, issue 3, pages 289-292
Published in print March 2005 | ISSN: 0305-7453
Published online March 2005 | e-ISSN: 1460-2091 | DOI: https://dx.doi.org/10.1093/jac/dkh558
Antiviral activity and molecular mechanism of an orally active respiratory syncytial virus fusion inhibitor

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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

Journal Article.  2848 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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