Identification of potent and selective mechanism-based inhibitors of the cysteine protease cruzain using solid-phase parallel synthesis
Identification of potent and selective mechanism-based inhibitors of the cysteine protease cruzain using solid-phase parallel synthesis
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DOI：
10.1021/jm010333m
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发表时间：
2002-01-31
影响因子：
7.3
通讯作者：
Ellman, JA
中科院分区：
文献类型：
--
作者：
Huang, L;Lee, A;Ellman, JA
合成基于酮的半胱氨酸蛋白酶抑制剂的靶向文库，并针对cruzain（一种与恰加斯病有关的半胱氨酸蛋白酶）进行筛选。鉴定了许多个位数纳摩尔、低分子量抑制剂，并针对溶解度和效力进行了优化。特别地，所鉴定的最佳抑制剂具有0.9-10 nM的Ki值和499 - 609 Da的分子量。还发现最有效的抑制剂相对于组织蛋白酶B对cruzain的选择性大于1000倍，相对于组织蛋白酶L对cruzain的选择性大于100倍。
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.