Structural characterization of the interactions of optimized product inhibitors with the N-terminal proteinase domain of the hepatitis C virus (HCV) NS3 protein by NMR and modelling studies

The interactions of peptide inhibitors, obtained by the optimization of N-t erminal cleavage products of natural substrates, with the protease of human hepatitis C virus (HCV) are characterized by NMR and modelling studies. Th e S-binding region of the enzyme and the bound conformation of the ligands are experimentally determined. The NMR data are then used as the experiment al basis for modelling studies of the structure of the complex. The S-bindi ng region involves the loop connecting strands E2 and F2, and appears shall ow and solvent-exposed. The ligand binds in an extended conformation, formi ng an antiparallel beta-sheet with strand E2 of the protein, with the P1 ca rboxylate group in the oxyanion hole. (C) 1999 Academic Press.