Structural Studies of the Complex Between Decapeptide Inhibitors and the Serine Protease NS3/4A of Hepatitis C Virus

One of the most promising approaches to anti-HCV therapy is the development of inhibitors of the viral NS3/4A protease, which is essential for maturation of the viral polyprotein. Several substrate-derived inhibitors have been described [1], all taking advantage of binding to the S site of the enzyme. By studying the interaction of these inhibitors with NS3 [2], we showed that binding occurs according to an induced-fit mechanism. In the absence of a cofactor, multiple binding modes are apparent, while in the presence of a cofactor all P-inhibitors show the same binding mode with a small rearrangement in the NS3 structure, as suggested by CD spectroscopy. Inhibitor complex formation is associated with stabilization of the enzyme, as highlighted by limited proteolysis experiments.