An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus (original) (raw)
References
- Choo, Q. L. et al. Isolation of a cDNA clone derived from a blood-borne non-A non-B viral hepatitis genome. Science 244, 359–362 (1989)
Article ADS CAS PubMed Google Scholar - Kuo, G. et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244, 362–364 (1989)
Article ADS CAS PubMed Google Scholar - Di Bisceglie, A. M. Hepatitis C. Lancet 351, 351–355 (1998)
Article CAS PubMed Google Scholar - Chander, G. et al. Treatment of chronic hepatitis C: a systematic review. Hepatology 36, S135 (2002)
ADS PubMed Google Scholar - Tan, S.-L., Pause, A., Shi, Y. & Sonenberg, N. Hepatitis C therapeutics: current status and emerging strategies. Nature Rev. Drug Discov. 1, 867–881 (2002)
Article CAS Google Scholar - Di Bisceglie, A. M., McHutchison, J. & Rice, C. M. New therapeutic strategies for hepatitis C. Hepatology 35, 224–231 (2002)
Article PubMed Google Scholar - Reed, K. E. & Rice, C. M. Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties. Curr. Top. Microbiol. Immunol. 242, 55–84 (2000)
CAS PubMed Google Scholar - Kolykhalov, A. A., Mihalik, K., Feinstone, S. M. & Rice, C. M. Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3′ nontranslated region are essential for virus replication in vivo. J. Virol. 74, 2046–2051 (2000)
Article CAS PubMed PubMed Central Google Scholar - Lohmann, V. et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285, 103–107 (1999)
Article Google Scholar - Mercer, D. F. et al. Hepatitis C virus replication in mice with chimeric human livers. Nature Med. 7, 927–933 (2001)
Article CAS PubMed Google Scholar - Schechter, I. & Berger, A. Protease subsite nomenclature. Biochem. Biophys. Res. Commun. 27, 157–162 (1967)
Article CAS PubMed Google Scholar - Llinàs-Brunet, M. et al. Peptide-based inhibitors of the hepatitis C virus serine protease. Bioorg. Med. Chem. Lett. 8, 1713–1718 (1998)
Article PubMed Google Scholar - Steinkühler, C. et al. Product inhibition of the hepatitis C virus NS3 protease. Biochemistry 37, 8899–8905 (1998)
Article PubMed Google Scholar - Llinàs-Brunet, M. et al. Studies on the C-terminal of hexapeptide inhibitors of the hepatitis C virus serine protease. Bioorg. Med. Chem. Lett. 8, 2719–2724 (1998)
Article PubMed Google Scholar - Llinàs-Brunet, M. et al. Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors. Bioorg. Med. Chem. Lett. 10, 2267–2270 (2000)
Article PubMed Google Scholar - Poupart, M.-A. et al. Solid-phase synthesis of peptidomimetic inhibitors for the hepatitis C virus NS3 protease. J. Org. Chem. 66, 4743–4751 (2001)
Article CAS PubMed Google Scholar - Goudreau, N. et al. NMR structural characterization of peptide inhibitors bound to the HCV NS3 protease: design of a new P2 substituent. J. Med. Chem. (submitted)
- Pause, A. et al. An NS3 serine protease inhibitor abrogates replication of subgenomic hepatitis C virus RNA. J. Biol. Chem. 278, 20374–20380 (2003)
Article CAS PubMed Google Scholar - LaPlante, S. R. et al. Solution structure of substrate-based ligands when bound to hepatitis C virus NS3 protease domain. J. Biol. Chem. 274, 18618–18624 (1999)
Article CAS PubMed Google Scholar - LaPlante, S. R. et al. NMR line-broadening and transferred NOESY as a medicinal chemistry tool for studying inhibitors of the hepatitis C virus NS3 protease domain. Bioorg. Med. Chem. Lett. 10, 2271–2274 (2000)
Article CAS PubMed Google Scholar - Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor tripeptides. US patent 6,323,180 B1 (2001).
- Tsantrizos, Y. et al. Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infection. Angew. Chem. Int. Edn Engl. 42, 1356–1360 (2003)
Article CAS Google Scholar - Narjes, H., Yong, C. L., Stahle, H. & Steinmann, G. Tolerability and pharmacokinetics of BILN 2061: a novel serine protease HCV inhibitor after oral single doses of 5 mg to 2,400 mg in healthy male subjects. Hepatology 36(4), Abst. 800 (2002)
Google Scholar - Hinrichsen, H. et al. First report on the antiviral efficacy of BILN 2061, a novel oral serine protease inhibitor, in patients with chronic hepatitis C genotype 1. Hepatology 36, 297A, Abst. 866 (2002)
Google Scholar - Benhamou, Y. et al. Safety, tolerability and antiviral effect of BILN 2061, a novel HCV serine protease inhibitor, after oral treatment over 2 days in patients with chronic hepatitis C, genotype 1, with advanced liver fibrosis. Hepatology 36, 304A, Abst. 563 (2002)
Google Scholar - Neumann, A. U. et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282, 103–107 (1998)
Article ADS CAS PubMed Google Scholar - Neumann, A. U. et al. Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus. J. Infect. Dis. 182, 28–35 (2000)
Article CAS PubMed Google Scholar - Zeuzem, S. et al. Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha 2a. Gastroenterology 120, 1438–1447 (2001)
Article CAS PubMed Google Scholar - Foy, E. et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300, 1145–1148 (2003)
Article ADS CAS PubMed Google Scholar - Boehringer Ingelheim (Canada) Ltd. Macrocyclic peptides active against the Hepatitis C virus. US patent 6,608,027 B1 (2003).
Acknowledgements
We wish to thank F. Dô, J. Duan, M. Garneau, N. Lapeyre-Paquette, S. Lefebvre, F. Liard, M. Marquis, R. Maurice, G. McKercher, A. Pause, C. Pellerin, L. Pilote, C. Plouffe and M. Rhéaume from the Biological Sciences Department, and N. Aubry, J. Bordeleau, C. Boucher, Y. Bousquet, C. Brochu, C. Chabot, R. Déziel, J.-S. Duceppe, G. Fazal, J.-M. Ferland, E. Ghiro, J. Gillard, V. Gorys, S. Goulet, C. Grand-Maître, B. Haché, T. Halmos, P. Lavallée, M. Little, E. Malenfant, R. Plante, M. Poirier, S. Valois and D. Wernic from the Chemistry Department. We also thank B. Willems and the Centre de Recherche Clinique André Viallet, Hôpital St-Luc, CHUM. We acknowledge the BILN 2061 development team and members of the departments of Drug Metabolism and Pharmacokinetics, Pharmacology, Pharmaceutics, Analytical Sciences, Process Chemistry, Toxicology, Drug Regulatory Affairs and Medical at Boehringer Ingelheim Pharmaceuticals, Inc., Connecticut, USA; J. Croenlein, G. Nehmiz and the clinical research teams at Boehringer Ingelheim Pharma KG, Biberach, Germany; and Academisch Medisch Centrum, The Netherlands. We thank the volunteers and patients who participated in the clinical trials of BILN 2061. R.E.S. was clinical investigator and received honorarium from Boehringer Ingelheim. All other authors are or were employees of Boehringer Ingelheim.
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- Dale R. Cameron
Present address: Micrologix Biotech Inc., BC Research Complex, 3650 Wesbrook Mall, Vancouver, British Columbia, V6S 2L2, Canada
Authors and Affiliations
- Departments of Biological Sciences Boehringer Ingelheim (Canada) Ltd, Laval, Québec, H7S 2G5, Canada
Daniel Lamarre, Gordon Bolger, Pierre Bonneau, Mireille Cartier, Michael G. Cordingley, George Kukolj, Lisette Lagacé & Diane Thibeault - Chemistry, Research and Development, Boehringer Ingelheim (Canada) Ltd, Laval, Québec, H7S 2G5, Canada
Paul C. Anderson, Murray Bailey, Pierre Beaulieu, Michael Bös, Dale R. Cameron, Anne-Marie Faucher, Nathalie Goudreau, Stephen H. Kawai, Steven R. LaPlante, Marc-André Poupart, Jean Rancourt, Bruno Simoneau, Youla S. Tsantrizos & Montse Llinàs-Brunet - Clinical Research, Boehringer Ingelheim Pharma KG, Biberach, 88397, Germany
Hans Narjes & Gerhard Steinmann - Academisch Medisch Center, Amsterdam, 1105 AZ, The Netherlands
Roel E. Sentjens - Research and Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, 06877-0368, USA
Roger St George, Steven M. Weldon & Chan-Loi Yong
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The authors have amended their Competing interests statement: it previously read 'The authors declare that they have no competing financial interests.' it should read ‘The authors declare competing financial interests: R.E.S. was the clinical investigator and received an honorarium from Boehringer Ingelheim. All the other authors are or were employees of Boehringer Ingelheim.’ A Corrigendum will soon be published.
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Lamarre, D., Anderson, P., Bailey, M. et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.Nature 426, 186–189 (2003). https://doi.org/10.1038/nature02099
- Received: 25 August 2003
- Accepted: 02 October 2003
- Published: 26 October 2003
- Issue Date: 13 November 2003
- DOI: https://doi.org/10.1038/nature02099