Identification of potent and selective mechanism-based inhibitors of the cysteine protease cruzain using solid-phase parallel synthesis

被引:54
作者
Huang, L [1 ]
Lee, A [1 ]
Ellman, JA [1 ]
机构
[1] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA
关键词
D O I
10.1021/jm010333m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Targeted libraries of ketone-based cysteine protease inhibitors were synthesized and screened against cruzain, a cysteine protease implicated in Chagas' disease. A number of single digit nanomolar, low molecular weight inhibitors were identified and optimized for solubility and potency. Specifically, the best inhibitors identified have K-i values of 0.9-10 nM and molecular weights between 499 and 609 Da. The most effective inhibitor was also found to be greater than 1000-fold selective for cruzain relative to cathepsin B and 100-fold selective for cruzain relative to cathepsin L.
引用
收藏
页码:676 / 684
页数:9
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