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‐acquired and sporadic non‐A, non‐B hepatitis worldwide. Infections most often persist and lead, in ≈ 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.