Journal Article

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

Rancourt, Jean, Anderson, Paul C., Weldon, Steven M., Tsantrizos, Youla S., Faucher, Anne-Marie, Bonneau, Pierre, Steinmann, Gerhard, Kawai, Stephen H., LaPlante, Steven R., St George, Roger, Narjes, Hans, Lagacé, Lisette, Poupart, Marc-André, Kukolj, George, Goudreau, Nathalie, Simoneau, Bruno, Sentjens, Roel E., Cameron, Dale R., Cartier, Mireille, Lamarre, Daniel, Bailey, Murray, Cordingley, Michael G., Bös, Michael, Llinàs-Brunet, Montse, Bolger, Gordon, Thibeault, Diane, Beaulieu, Pierre, Yong, Chan-Loi

2003

Overview

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 1 , 2 , 3 . Current interferon-based therapies 4 are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics 5 , 6 . The HCV-encoded NS3 protease is essential for viral replication 7 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Administration, Oral / Antibiotics. Antiinfectious agents. Antiparasitic agents / Antiviral agents / Antiviral Agents - administration & dosage / Antiviral Agents - pharmacokinetics / Antiviral Agents - pharmacology / Antiviral Agents - therapeutic use / Biological and medical sciences / Carbamates - administration & dosage / Carbamates - chemistry / Carbamates - pharmacokinetics / Carbamates - pharmacology / Double-Blind Method / Drug therapy / Enzymes / Hepacivirus - drug effects / Hepacivirus - enzymology / Hepacivirus - genetics / Hepacivirus - physiology / Hepatitis / Hepatitis C - drug therapy / Hepatitis C - virology / Human viral diseases / Humanities and Social Sciences / Humans / Infectious diseases / Ingestion / letter / Macrocyclic Compounds / Male / Medical sciences / multidisciplinary / Pharmacology. Drug treatments / Polyproteins - metabolism / Protein Processing, Post-Translational - drug effects / Proteinase inhibitors / Quinolines / Science / Science (multidisciplinary) / Serine Proteinase Inhibitors - administration & dosage / Serine Proteinase Inhibitors - pharmacokinetics / Serine Proteinase Inhibitors - pharmacology / Serine Proteinase Inhibitors - therapeutic use / Thiazoles - administration & dosage / Thiazoles - chemistry / Thiazoles - pharmacokinetics / Thiazoles - pharmacology / Viral diseases / Viral hepatitis / Viral Load / Viral Nonstructural Proteins - antagonists & inhibitors / Viral Nonstructural Proteins - metabolism / Viral Proteins - metabolism / Viruses