Macrocyclic Inhibitors of HCV NS3-4A Protease: Design and Structure Activity Relationship

Authors: Srikanth Venkatraman,; F. George Njoroge,

Source: Current Topics in Medicinal Chemistry, Volume 7, Number 13, July 2007 , pp. 1290-1301(12)

Publisher: Bentham Science Publishers

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Abstract:

HCV NS3, a serine protease, that when bound to NS-4A cofactor facilitates development of mature virons by catalyzing cleavage of a single polyprotein to form functional and structural proteins of HCV. X-ray structure of the enzyme reveal a very shallow binding pocket at the catalytic site which makes development of inhibitors a daunting task. Various novel approaches have been used to design, preorganized, depeptidized macrocyclic inhibitors linking the P2-P4 residues and P1-P3 groups. The design and structure activity relationship of these macrocyclic inhibitors are reviewed in the following article. X-ray structure of inhibitor bound to the active site of the enzyme is also discussed. Macrocyclization proved to be an effective tool for depeptidization of peptidic inhibitors, imparting enhanced metabolic stability and improved pharmacokinetic properties in the resultant molecules.

Keywords: Macrocyclization; HCV; NS3 protease; BILN-2061; depeptidization

Document Type: Research article

Affiliations: 1: MS 3545, K15, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033.

Publication date: 2007-07-01