Letters to Nature
Nature 426, 186-189 (13 November 2003) | doi:10.1038/nature02099; Received 25 August 2003; Accepted 2 October 2003; Published online 26 October 2003
An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus
Daniel Lamarre1, Paul C. Anderson2, Murray Bailey2, Pierre Beaulieu2, Gordon Bolger1, Pierre Bonneau1, Michael Bös2, Dale R. Cameron2,6, Mireille Cartier1, Michael G. Cordingley1, Anne-Marie Faucher2, Nathalie Goudreau2, Stephen H. Kawai2, George Kukolj1, Lisette Lagacé1, Steven R. LaPlante2, Hans Narjes3, Marc-André Poupart2, Jean Rancourt2, Roel E. Sentjens4, Roger St George5, Bruno Simoneau2, Gerhard Steinmann3, Diane Thibeault1, Youla S. Tsantrizos2, Steven M. Weldon5, Chan-Loi Yong5 and Montse Llinàs-Brunet2
- Departments of Biological Sciences Boehringer Ingelheim (Canada) Ltd, Laval, Québec, H7S 2G5, Canada
- Chemistry, Research and Development, Boehringer Ingelheim (Canada) Ltd, Laval, Québec, H7S 2G5, Canada
- Clinical Research, Boehringer Ingelheim Pharma KG, Biberach 88397, Germany
- Academisch Medisch Center, 1105 AZ, Amsterdam, The Netherlands
- Research and Development, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877-0368, USA
- Present address: Micrologix Biotech Inc., BC Research Complex, 3650 Wesbrook Mall, Vancouver, British Columbia, V6S 2L2, Canada
Correspondence to: Daniel Lamarre1 Email: dlamarre@lav.boehringer-ingelheim.com
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.