基于结构的药物设计用于设计和合成丙型肝炎NS3-4A蛋白酶的去肽大环抑制剂。

Design and synthesis of depeptidized macrocyclic inhibitors of hepatitis C NS3-4A protease using structure-based drug design.

作者信息

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

机构信息

Schering Plough Research Institute, K-15, MS-3545, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

出版信息

J Med Chem. 2005 Aug 11;48(16):5088-91. doi: 10.1021/jm0489556.

DOI:10.1021/jm0489556

PMID:16078825

Abstract

Hepatitis 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 P(4) to P(2)' and optimized binding to 0.1 microM. The structure of an inhibitor bound to the enzyme was also solved.

摘要

丙型肝炎病毒（HCV）的NS3蛋白与NS-4A辅助因子结合时，通过催化多蛋白的裂解形成HCV的功能蛋白和结构蛋白，促进成熟病毒体的形成。该酶在催化位点有一个浅的结合口袋，使得抑制剂的研发具有挑战性。我们设计、预组织并去肽化了从P(4)到P(2)'的大环抑制剂，并将结合亲和力优化至0.1微摩尔。还解析了一种与该酶结合的抑制剂的结构。