Design and synthesis of depeptidized macrocyclic inhibitors of hepatitis C NS3-4A protease using structure-based drug design.
Design and synthesis of depeptidized macrocyclic inhibitors of hepatitis C NS3-4A protease using structure-based drug design.
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DOI：
10.1021/jm0489556
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发表时间：
2005-07
影响因子：
7.3
通讯作者：
S. Venkatraman;F. Njoroge;V. Girijavallabhan;V. Madison;N. H. Yao;A. Prongay;N. Butkiewicz;J. Pichardo
中科院分区：
文献类型：
--
作者：
S. Venkatraman;F. Njoroge;V. Girijavallabhan;V. Madison;N. H. Yao;A. Prongay;N. Butkiewicz;J. Pichardo
丙型肝炎病毒（HCV）NS 3在与NS-4A辅因子结合时，通过催化多蛋白裂解以形成HCV的功能和结构蛋白而促进成熟病毒子的发育。该酶在催化位点有一个浅的结合口袋，使得抑制剂的开发变得困难。我们已经设计、预组织和去肽化了从P（4）到P（2）'的大环抑制剂，并优化了与0.1 μ M的结合。与酶结合的抑制剂的结构也得到了解决。
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.