Search

Much effort for a therapy against hepatitis C virus (HCV) is devoted to the search of inhibitors of the virally-encoded protease NS3, which is required for maturation of HCV polyprotein [1]. In order to cleave its substrates NS3 must form a complex with the 54residue viral cofactor protein NS4A, whose activity is mimicked by a synthetic peptide (Pep4A) corresponding to amino acids 21-34 [1]. Binding of Pep4A was shown to induce important tertiary structure changes in the enzyme [2]. We have recently developed substrate-derived hexapeptide inhibitors of NS3 with affinities in the low nanomolar range [3]. Structure-activity relationships, molecular modelling, site-directed mutagenesis and most recently NMR have been used to gain knowledge about the salient features of inhibitor binding [3-5]. In the present work we have further studied the interaction between NS3, NS4A and the inhibitors, and found that major conformational changes take place in the enzyme upon binary and ternary complex formation.