title: Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus.
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.
authors.affiliation: Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Morikawa
authors.forename: C M
authors.initials: CM
authors.lastname: Lange
authors.forename: J
authors.initials: J
authors.lastname: Gouttenoire
authors.forename: E
authors.initials: E
authors.lastname: Meylan
authors.forename: V
authors.initials: V
authors.lastname: Brass
authors.forename: F
authors.initials: F
authors.lastname: Penin
authors.forename: D
authors.initials: D
authors.lastname: Moradpour
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D024882:Drug Resistance, Viral / Q000235:genetics; D016174:Hepacivirus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D043583:Nucleoside-Triphosphatase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000378:metabolism; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057057:Serine Proteases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication; D012697:Serine Endopeptidases; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D043583:Nucleoside-Triphosphatase; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D020365:RNA Helicases; D057057:Serine Proteases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C505371:MAVS protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C470409:TICAM1 protein, human