An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus
- Lamarre, Daniel
- Anderson, Paul C.
- Bailey, Murray
- Beaulieu, Pierre
- Bolger, Gordon
- Bonneau, Pierre
- Bös, Michael
- Cameron, Dale R.
- Cartier, Mireille
- Cordingley, Michael G.
- Faucher, Anne-Marie
- Goudreau, Nathalie
- Kawai, Stephen H.
- Kukolj, George
- Lagacé, Lisette
- LaPlante, Steven R.
- Narjes, Hans
- Poupart, Marc-André
- Rancourt, Jean
- Sentjens, Roel E.
- St George, Roger
- Simoneau, Bruno
- Steinmann, Gerhard
- Thibeault, Diane
- Tsantrizos, Youla S.
- Weldon, Steven M.
- Yong, Chan-Loi
- Llinàs-Brunet, Montse
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 mortality. Current interferon-based therapiesare suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replicationand 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.