Article

Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics.

Pharmasset, Inc., Princeton, NJ 08540, USA.
Bioorganic & medicinal chemistry letters (impact factor: 2.65). 02/2012; 22(8):2938-42. DOI:10.1016/j.bmcl.2012.02.051 pp.2938-42
Source: PubMed

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.

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Keywords

clinic evaluation
 
computational modeling studies strong intra-molecular hydrogen bonds
 
inhibitor exhibited picomolar activity
 
low pico-molar replicon potency
 
measurable cytotoxicity
 
natural peptide-based inhibitors
 
novel NS5A inhibitor
 
NS5A inhibitors
 
peptidomimetic approach
 
structurally unique inhibitors
 
viable target
 

Wonsuk Chang