Abstract
Hepatitis C virus (HCV) nonstructural protein 3-4A (NS3-4A) is a complex composed of NS3 and its cofactor NS4A. It harbours serine protease as well as NTPase/RNA helicase activities and is essential for viral polyprotein processing, RNA replication and virion formation. Specific inhibitors of the NS3-4A protease significantly improve sustained virological response rates in patients with chronic hepatitis C when combined with pegylated interferon-α and ribavirin. The NS3-4A protease can also target selected cellular proteins, thereby blocking innate immune pathways and modulating growth factor signalling. Hence, NS3-4A is not only an essential component of the viral replication complex and prime target for antiviral intervention but also a key player in the persistence and pathogenesis of HCV. This review provides a concise update on the biochemical and structural aspects of NS3-4A, its role in the pathogenesis of chronic hepatitis C and the clinical development of NS3-4A protease inhibitors.
© 2011 Blackwell Publishing Ltd.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Adaptor Proteins, Vesicular Transport / metabolism
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Antiviral Agents / pharmacology
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Antiviral Agents / therapeutic use
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Drug Resistance, Viral / genetics
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Hepacivirus / enzymology
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Hepacivirus / genetics
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Hepacivirus / metabolism*
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Hepatitis C, Chronic / drug therapy
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Hepatitis C, Chronic / virology*
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Humans
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins / antagonists & inhibitors
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Mitochondrial Proteins / chemistry
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Mutation
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Nucleoside-Triphosphatase / antagonists & inhibitors
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Nucleoside-Triphosphatase / chemistry
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Nucleoside-Triphosphatase / genetics
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Nucleoside-Triphosphatase / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism
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RNA Helicases / antagonists & inhibitors
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RNA Helicases / chemistry
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RNA Helicases / genetics
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RNA Helicases / metabolism
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Serine Proteases / chemistry
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Serine Proteases / genetics
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Serine Proteases / metabolism
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Serine Proteinase Inhibitors / pharmacology
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Serine Proteinase Inhibitors / therapeutic use
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Signal Transduction
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Viral Nonstructural Proteins / antagonists & inhibitors
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Viral Nonstructural Proteins / chemistry
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Viral Nonstructural Proteins / genetics
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Viral Nonstructural Proteins / metabolism*
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Virus Replication
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Antiviral Agents
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Carrier Proteins
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Intracellular Signaling Peptides and Proteins
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MAVS protein, human
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Mitochondrial Proteins
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NS3 protein, hepatitis C virus
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NS4A cofactor peptide, Hepatitis C virus
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Serine Proteinase Inhibitors
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TICAM1 protein, human
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Viral Nonstructural Proteins
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Protein Tyrosine Phosphatase, Non-Receptor Type 2
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Serine Proteases
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Nucleoside-Triphosphatase
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RNA Helicases