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Journal of Virology, July 2004, p. 7352-7359, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7352-7359.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Sensitivity of NS3 Serine Proteases from Hepatitis C Virus Genotypes 2 and 3 to the Inhibitor BILN 2061

Diane Thibeault,1* Christiane Bousquet,1 Rock Gingras,1 Lisette Lagacé,1 Roger Maurice,1 Peter W. White,1 and Daniel Lamarre1,{dagger}

Department of Biological Sciences, Boehringer Ingelheim (Canada) Ltd., Research and Development, Laval, Québec H7S 2G5, Canada1

Received 3 February 2004/ Accepted 12 March 2004

Hepatitis C virus (HCV) displays a high degree of genetic variability. Six genotypes and more than 50 subtypes have been identified to date. In this report, kinetic profiles were determined for NS3 proteases of genotypes 1a, 1b, 2ac, 2b, and 3a, revealing no major differences in activity. In vitro sensitivity studies with BILN 2061 showed a decrease in affinity for proteases of genotypes 2 and 3 (Ki, 80 to 90 nM) compared to genotype 1 enzymes (Ki, 1.5 nM). To understand the reduced sensitivity of genotypes 2 and 3 to BILN 2061, active-site residues in the proximity of the inhibitor binding site were replaced in the genotype-1b enzyme with the corresponding genotype-2b or -3a residues. The replacement of five residues at positions 78, 79, 80, 122, and 132 accounted for most of the reduced sensitivity of genotype 2b, while replacement of residue 168 alone could account for the reduced sensitivity of genotype 3a. BILN 2061 remains a potent inhibitor of these non-genotype-1 NS3-NS4A proteins, with Ki values below 100 nM. This in vitro potency, in conjunction with the good pharmacokinetic data reported for humans, suggests that there is potential for BILN 2061 as an antiviral agent for individuals infected with non-genotype-1 HCV.

* Corresponding author. Mailing address: Department of Biological Sciences, Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard St., Laval, Québec H7S 2G5, Canada. Phone: (450) 682-4640. Fax: (450) 682-8434. E-mail: dthibeault{at}lav.boehringer-ingelheim.com.

{dagger} Present address: Département de Médecine, Université de Montréal and Centre de Recherche du CHUM, Montréal, Québec H2X 1P1, Canada.

Journal of Virology, July 2004, p. 7352-7359, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7352-7359.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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