Hepatitis C virus serine protease inhibitors: Current progress and future challenges

Hepatitis C is a predominantly chronic viral infection, affecting 1-3% of t he world population. The causative agent, the hepatitis C virus (HCV), has a positive strand-RNA genome that is utilized, in infected cells, as an mRN A to drive the synthesis of a large polyprotein precursor. This precursor s ubsequently undergoes proteolytic maturation to generate all of the functio nal, both structural and nonstructural proteins necessary for viral replica tion and assembly. The proteolytic activity that is responsible for the gen eration of the mature viral polymerase as well as for most of the cleavages occurring in the nonstructural region of the polyprotein is expressed by t he virus itself and is contained in its nonstructural protein 3 (NS3). Here , the N-terminal 180 amino acids form a chymotrypsin-like serine protease d omain. Full activation of this protease is achieved only after complexation with another viral protein, the cofactor protein NS4A. Together, NS3 and N S4A form the active, heterodimeric serine protease that presently is the ta rget of medicinal chemistry efforts aiming at the development of inhibitors with potential antiviral activity. We here review the recent progress in o ur understanding of the structure and function of the enzyme and in the dev elopment of selective and potent NS3 protease inhibitors.