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

The hepatitis C virus (HCV) is a major causative agent of transfusion-acqui red and sporadic non-A, non-B hepatitis worldwide. Infections most often pe rsist and lead, in approximate to 50% of all patients, to chronic liver dis ease. 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 p roteinase 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 de scribe the biochemical properties of the NS 3 /4A proteinase, its X-ray cry stal structure, and current attempts towards development of efficient inhib itors.