Solution structure of substrate-based ligands when bound to hepatitis C virus NS3 protease domain

The interactions of the NS3 protease domain with inhibitors that are based on N-terminal cleavage products of peptide substrates were studied by NMR m ethods. Transferred nuclear Overhauser effect experiments showed that these inhibitors bind the protease in a well defined, extended conformation. Pro tease-induced line-broadening studies helped identify the segments of inhib itors which come into contact with the protease. A comparison of the NMR da ta of the free and protease-bound states suggests that these ligands underg o rigidification upon complexation. This work provides the first structure of an inhibitor when bound to NS3 protease and should be valuable for desig ning more potent inhibitors.