Abstract
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.
Publication types
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Clinical Trial
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Clinical Trial, Phase I
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Controlled Clinical Trial
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Antiviral Agents / administration & dosage
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology
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Antiviral Agents / therapeutic use*
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Carbamates / administration & dosage
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Carbamates / chemistry
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Carbamates / pharmacokinetics
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Carbamates / pharmacology*
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Double-Blind Method
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Hepacivirus / drug effects*
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Hepacivirus / enzymology
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Hepacivirus / genetics
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Hepacivirus / physiology*
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Hepatitis C / drug therapy*
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Hepatitis C / virology
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Humans
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Macrocyclic Compounds*
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Male
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Polyproteins / metabolism
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Protein Processing, Post-Translational / drug effects
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Quinolines*
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Serine Proteinase Inhibitors / administration & dosage
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Serine Proteinase Inhibitors / pharmacokinetics
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Serine Proteinase Inhibitors / pharmacology
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Serine Proteinase Inhibitors / therapeutic use*
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Thiazoles / administration & dosage
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Thiazoles / chemistry
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology*
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Viral Load
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / metabolism
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Viral Proteins / metabolism
Substances
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Antiviral Agents
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BILN 2061
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Carbamates
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Macrocyclic Compounds
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NS3 protein, hepatitis C virus
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Polyproteins
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Quinolines
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Serine Proteinase Inhibitors
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Thiazoles
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Viral Nonstructural Proteins
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Viral Proteins