DOI: 10.1128/jvi.78.14.7352-7359.2004. Sensitivity of NS3 Serine Proteases from Hepatitis C Virus Genotypes 2 and 3 to the Inhibitor BILN 2061

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

10.1128/jvi.78.14.7352-7359.2004

Crossref journal-article

American Society for Microbiology

Journal of Virology (235)

Abstract

ABSTRACTHepatitis 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, withKivalues 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.

Bibliography

Thibeault, D., Bousquet, C., Gingras, R., LagaceÌ, L., Maurice, R., White, P. W., & Lamarre, D. (2004). Sensitivity of NS3 Serine Proteases from Hepatitis C Virus Genotypes 2 and 3 to the Inhibitor BILN 2061. Journal of Virology, 78(14), 7352â7359.

Authors 7

Diane Thibeault (first)
Christiane Bousquet (additional)
Rock Gingras (additional)
Lisette Lagacé (additional)
Roger Maurice (additional)
Peter W. White (additional)
Daniel Lamarre (additional)

References 33 Referenced 74

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Di Bisceglie, A. M., and J. H. Hoofnagle. 2002. Optimal therapy of hepatitis C. Hepatology36:S121-S127. (10.1002/hep.1840360716) / Hepatology (2002)
Domingo, E., C. M. Ruiz-Jarabo, S. Sierra, A. Arias, N. Pariente, E. Baranowski, and C. Escarmís. 2002. Emergence and selection of RNA virus variants: memory and extinction. Virus Res.82:39-44. / Virus Res. (2002)
10.1073/pnas.96.24.13910
Hoofnagle, J. H. 2002. Course and outcome of hepatitis C. Hepatology36:S21-S29. (10.1002/hep.1840360704) / Hepatology (2002)
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Dates

Type	When
Created	21 years, 2 months ago (June 25, 2004, 3:18 p.m.)
Deposited	8 months, 1 week ago (Dec. 17, 2024, 2:02 p.m.)
Indexed	5 months ago (March 26, 2025, 1:40 p.m.)
Issued	21 years, 1 month ago (July 15, 2004)
Published	21 years, 1 month ago (July 15, 2004)
Published Print	21 years, 1 month ago (July 15, 2004)

Funders 0

None

BibTeX

@article{Thibeault_2004, title={Sensitivity of NS3 Serine Proteases from Hepatitis C Virus Genotypes 2 and 3 to the Inhibitor BILN 2061}, volume={78}, ISSN={1098-5514}, url={http://dx.doi.org/10.1128/jvi.78.14.7352-7359.2004}, DOI={10.1128/jvi.78.14.7352-7359.2004}, number={14}, journal={Journal of Virology}, publisher={American Society for Microbiology}, author={Thibeault, Diane and Bousquet, Christiane and Gingras, Rock and Lagacé, Lisette and Maurice, Roger and White, Peter W. and Lamarre, Daniel}, year={2004}, month=jul, pages={7352–7359} }

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