Induced-Fit Binding of the Macrocyclic Noncovalent Inhibitor TMC435 to its HCV NS3/NS4A Protease Target

摘要

The NS3 protein of hepatitis C virus (HCV), together with the NS4A peptide co-factor, comprises 685 residues and possesses domain-specific RNA helicase and serine protease activities. NS3/NS4A protease activity is essential to the HCV life cycle. Small-molecule inhibitors of NS3/NS4A protease have been widely explored and are typically grouped into two classes: linear peptidomimetics with a ketoamide functionality that reacts with the catalytic Ser to form a reversible enzyme-inhibitor adduct, and noncovalent peptidomimetics containing a macrocycle (e.g. Figure 1); macrocyclic ketoamide inhibitors have also been reported.