Department of Biochemistry School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Adv Parasitol. 2011;75:65-87. doi: 10.1016/B978-0-12-385863-4.00004-6.
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.
针对特定代谢途径/酶进行药物开发时，至少有两个明显的特征必须考虑：该途径必须是必需的，并且该酶必须允许设计具有药理用途的抑制剂。在这里，我们将克氏锥虫固醇 14α-脱甲基酶描述为抗恰加斯病化疗的有前途的靶标。抗真菌唑类药物（阻断固醇生物合成，从而阻断真菌中的膜形成）用于原生动物寄生虫已被证明非常成功：一种广谱抗真菌药物，三唑化合物泊沙康唑，目前正在进入治疗恰加斯病的 II 期临床试验。本综述通过对靶酶的最近结构/功能特征的描述，总结了抗真菌唑类药物和新型选择性抑制锥虫固醇 14α-脱甲基酶的抑制支架的比较信息。我们相信我们的研究为合理设计新型、针对病原体的、因此更有效和高效的抗锥虫药物开辟了广阔的机会。
