Design and Synthesis of Depeptidized Macrocyclic Inhibitors of Hepatitis C NS3-4A Protease Using Structure-Based Drug Design

J. Med. Chem., 48 (16), 5088 -5091, 2005. 10.1021/jm0489556 S0022-2623(04)08955-1
Web Release Date: July 14, 2005

Design and Synthesis of Depeptidized Macrocyclic Inhibitors of Hepatitis C NS3-4A Protease Using Structure-Based Drug Design

Srikanth Venkatraman,* F. George Njoroge, Viyyoor M. Girijavallabhan, Vincent S. Madison, Nanua H. Yao, Andrew J. Prongay, Nancy Butkiewicz, and John Pichardo

Schering Plough Research Institute, K-15, MS-3545, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033

Received December 23, 2004

Abstract:

Hepatitus C virus (HCV) NS3, when bound to NS-4A cofactor, facilitates development of mature virons by catalyzing cleavage of a polyprotein to form functional and structural proteins of HCV. The enzyme has a shallow binding pocket at the catalytic site, making development of inhibitors difficult. We have designed, preorganized, and depeptidized macrocyclic inhibitors from P₄ to P₂' and optimized binding to 0.1 M. The structure of an inhibitor bound to the enzyme was also solved.

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