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An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.

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

Department of Biological Sciences Boehringer Ingelheim (Canada) Ltd, Laval, Québec, H7S 2G5, Canada. 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 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.

Nature 2003;426(6963):186-9.

Pubmed ID: 14578911

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