The NS3/4A proteinase of the hepatitis C virus: unravelling structure and function of an unusual enzyme and a prime target for antiviral therapy

J Viral Hepat. 1999 May;6(3):165-81. doi: 10.1046/j.1365-2893.1999.00152.x.


The hepatitis C virus (HCV) is a major causative agent of transfusion-acquired and sporadic non-A, non-B hepatitis worldwide. Infections most often persist and lead, in approximately 50% of all patients, to chronic liver disease. As is characteristic for a member of the family Flaviviridae, HCV has a plus-strand RNA genome encoding a polyprotein, which is cleaved co- and post-translationally into at least 10 different products. These cleavages are mediated, among others, by a virally encoded chymotrypsin-like serine proteinase located in the N-terminal domain of non-structural protein 3 (NS3). Activity of this enzyme requires NS4A, a 54-residue polyprotein cleavage product, to form a stable complex with the NS3 domain. This review will describe the biochemical properties of the NS3/4A proteinase, its X-ray crystal structure and current attempts towards development of efficient inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / pharmacology
  • Hepacivirus / drug effects
  • Hepacivirus / enzymology*
  • Hepacivirus / genetics
  • Models, Molecular
  • Molecular Sequence Data
  • Protease Inhibitors / pharmacology
  • Protein Conformation
  • RNA Helicases
  • Serine Endopeptidases
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism


  • Antiviral Agents
  • NS3 protein, flavivirus
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • Serine Endopeptidases
  • RNA Helicases