Lamarre, D; Anderson, PC; Bailey, M; Beaulieu, P; Bolger, G; Bonneau, P; Bös, M; Cameron, DR; Cartier, M; Cordingley, MG; Faucher, AM; Goudreau, N; Kawai, SH; Kukolj, G; Lagacé, L; Laplante, , SR; Narjes, H; Poupart, MA; Rancourt, J; Sentjens, RE; St George, R; Simoneau, B; Steinmann, G; Thibeault, D; Tsantrizos, YS; Weldon, SM; Yong, CL; Llinàs-Brunet, M
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 therapies are 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 replication 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.