Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality1,2,3. Current interferon-based therapies4 are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics5,6. The HCV-encoded NS3 protease is essential for viral replication7,8 and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.
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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.
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
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