Macrocyclic inhibitors of HCV NS3 protease.

Background: HCV NS3 is a serine protease that plays a pivotal role in catalyzing the cleavage of the single polyprotein encoded by HCV after infection of hepatocytes. Analysis of the X-ray crystal structure of the enzyme reveals a shallow catalytic site located on the surface of the protein, which has made development of inhibitors a formidable task. Attempts to discover leads by a traditional approach of screening of compound libraries have proved futile and, therefore, researchers have adopted a structure-based drug design. Analysis of the X-ray structure of NS3 protease reveals close proximity of S(1)-S(3) and S(2)-S(4) pockets. Various novel approaches have been used to design preorganized, depeptidized macrocyclic inhibitors linking the P(2)-P(4) groups and P(1)-P(3) residues.

Objective: The article summarizes efforts by various groups to develop inhibitors that bind to the active site and inhibit viral replication.

Method: Review of recent patents and scientific literature.

Conclusion: Macrocyclization has proved to be an effective tool for depeptidization of peptidic inhibitors with improved binding and pharmacokinetic properties.