DESIGN OF SELECTIVE EGLIN INHIBITORS OF HCV NS3 PROTEINASE

Hepatitis C virus (HCV) infection is a major health problem that leads to cirrhosis and hepatocellular carcinoma in a substantial number of infected individuals, estimated to be 100-200 million worldwide. Unfor tunately, immunotherapy or other effective treatments fbr HCV infectio n are not yet available, and interferon administration has limited eff icacy. Different approaches to HCV therapy are being explored, and the se include inhibition of the viral proteinase, helicase, and RNA-depen dent RNA polymerase and development of a vaccine. Here we present the design of selective inhibitors with nanomolar potencies of HCV NS3 pro teinase based on eglin c, These eglin c mutants were generated by resh aping the inhibitor active site-binding loop, and the results emphasiz e the role played by residues P5-P4' in enzyme recognition. In additio n, alanine scanning experiments provide evidence that the N terminus o f eglin c also contributes to NS3 binding. These eglin inhibitors offe r a unique tool for accurately assessing the requirements for effectiv e inhibition of the enzymatic activity of NS3 and at the same time can be considered lead compounds for the identification of other NS3 inhi bitors in targeted design efforts.