Targeting Trypanosoma cruzi sterol 14α-demethylase (CYP51).
Targeting Trypanosoma cruzi sterol 14α-demethylase (CYP51).
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DOI：
10.1016/b978-0-12-385863-4.00004-6
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发表时间：
2011
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.;Villalta, Fernando;Waterman, Michael R.
在靶向特定的代谢途径/酶用于药物开发时，必须考虑至少两个明显的特征：该途径必须是必需的，并且酶必须允许设计可重复使用的抑制剂。在这里，我们描述了克氏锥虫甾醇14α-脱甲基酶作为一个有前途的目标，抗Chagillin化疗。使用抗真菌唑类（其阻断固醇生物合成并因此阻断真菌中的膜形成）对抗原生动物寄生虫已证明是非常成功的：广谱抗真菌药物三唑化合物泊沙康唑现在正进入治疗恰加斯病的II期临床试验。本文通过对锥虫甾醇14α-脱甲基酶结构/功能表征的透镜，综述了抗真菌唑类化合物和新型抑制性支架的比较信息。我们相信我们的研究为合理设计新颖的、病原体特异性的、因此更有效的抗锥虫药物提供了广泛的机会。
There are at least two obvious features that must be considered upon targeting specific metabolic pathways/enzymes for drug development: the pathway must be essential and the enzyme must allow the design of pharmacologically useful inhibitors. Here, we describe Trypanosoma cruzi sterol 14α-demethylase as a promising target for anti-Chagasic chemotherapy. The use of anti-fungal azoles, which block sterol biosynthesis and therefore membrane formation in fungi, against the protozoan parasite has turned out to be highly successful: a broad spectrum anti-fungal drug, the triazole compound posaconazole, is now entering phase II clinical trials for treatment of Chagas disease. This review summarizes comparative information on anti-fungal azoles and novel inhibitory scaffolds selective for Trypanosomatidae sterol 14α-demethylase through the lens of recent structure/functional characterization of the target enzyme. We believe our studies open wide opportunities for rational design of novel, pathogen-specific and therefore more potent and efficient anti-trypanosomal drugs.