Sterol 14α-demethylase as a potential target for antitrypanosomal therapy:: Enzyme inhibition and parasite cell growth
Sterol 14α-demethylase as a potential target for antitrypanosomal therapy:: Enzyme inhibition and parasite cell growth
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DOI：
10.1016/j.chembiol.2007.10.011
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发表时间：
2007-11-01
影响因子：
--
通讯作者：
Waterman, Michael R.
中科院分区：
文献类型：
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作者：
Lepesheva, Galina I.;Ott, Robert D.;Waterman, Michael R.
甾醇14α-去甲基酶(CyP51)是抗真菌药物的主要靶点，对原虫布氏锥虫(TB)和克氏锥虫(TC)中的CyP51的特异性抑制可能为治疗人类锥虫病提供一种有效的策略。初级抑制剂的选择最初基于细胞色素P450对配体结合的光谱反应。显示最强结合参数的配体被检测为体外重组TB和TC CYP51活性的抑制剂。这些化合物作为CYP51抑制剂的效力与它们在TB和TC细胞中的抗寄生虫作用之间的直接相关性表明，这两个锥虫体内内源性类固醇的产生是必要的，并暗示了一个具有明确区域的铅结构，最有希望进行进一步的修饰。该方法可用于进一步大规模寻找新的细胞色素P51抑制剂。
Sterol 14 alpha-demethylases (CYP51) serve as primary targets for antifungal drugs, and specific inhibition of CYP51s in protozoan parasites Trypanosoma brucei (TB) and Trypanosoma cruzi (TC) might provide an effective treatment strategy for human trypanosomiases. Primary inhibitor selection is based initially on the cytochrome P450 spectral response to ligand binding. Ligands that demonstrate strongest binding parameters were examined as inhibitors of reconstituted TB and TC CYP51 activity in vitro. Direct correlation between potency of the compounds as CYP51 inhibitors and their antiparasitic effect in TB and TC cells implies essential requirements for endogenous sterol production in both trypanosomes and suggests a lead structure with a defined region most promising for further modifications. The approach developed here can be used for further large-scale search for new CYP51 inhibitors.