title: Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics.
abstract: The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-molecular hydrogen bonds were found to be a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin containing inhibitor exhibited picomolar activity (EC(50)=79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.
authors.affiliation: Pharmasset, Inc., Princeton, NJ 08540, USA. wochang@gmail.com
authors.forename: Wonsuk
authors.initials: W
authors.lastname: Chang
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Mosley
authors.forename: Shalini
authors.initials: S
authors.lastname: Bansal
authors.forename: Meg
authors.initials: M
authors.lastname: Keilman
authors.forename: Angela M
authors.initials: AM
authors.lastname: Lam
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Furman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sofia
mesh_terms: D000475:Alkenes / Q000737:chemistry* / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry* / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000475:Alkenes; D005461:Fluorine; D057786:Peptidomimetics; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase