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Journal of Virology, July 2007, p. 6909-6919, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.01543-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Binding-Site Identification and Genotypic Profiling of Hepatitis C Virus Polymerase Inhibitors{triangledown}

Frederik Pauwels, Wendy Mostmans, Ludo M. M. Quirynen, Liesbet van der Helm, Carlo W. Boutton, Anne-Stéphanie Rueff, Erna Cleiren, Pierre Raboisson, Dominique Surleraux, Origène Nyanguile,* and Kenneth A. Simmen

HCV Research, Tibotec, Mechelen, Belgium

Received 19 July 2006/ Accepted 11 April 2007

The search for hepatitis C virus polymerase inhibitors has resulted in the identification of several nonnucleoside binding pockets. The shape and nature of these binding sites differ across and even within diverse hepatitis C virus genotypes. These differences confront antiviral drug discovery with the challenge of finding compounds that are capable of inhibition in variable binding pockets. To address this, we have established a hepatitis C virus mutant and genotypic recombinant polymerase panel as a means of guiding medicinal chemistry through the elucidation of the site of action of novel inhibitors and profiling against genotypes. Using a genotype 1b backbone, we demonstrate that the recombinant P495L, M423T, M414T, and S282T mutant enzymes can be used to identify the binding site of an acyl pyrrolidine analog. We assess the inhibitory activity of this analog and other nonnucleoside inhibitors with our panel of enzyme isolates generated from clinical sera representing genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a.

* Corresponding author. Mailing address: Tibotec BVBA, Generaal de Wittelaan L11B 3, 2800 Mechelen, Belgium. Phone: 32 15 401 296. Fax: 32 15 286 347. E-mail: onyangui{at}tibbe.jnj.com

{triangledown} Published ahead of print on 25 April 2007.

Journal of Virology, July 2007, p. 6909-6919, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.01543-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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