基于甾醇 14α-脱甲基酶结构的人源原生动物锥虫感染候选药物的优化。
Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae.
机构信息
Department of Biochemistry , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States.
Department of Microbiology, Immunology and Physiology , Meharry Medical College , Nashville , Tennessee 37208 , United States.
出版信息
J Med Chem. 2018 Dec 13;61(23):10910-10921. doi: 10.1021/acs.jmedchem.8b01671. Epub 2018 Nov 30.
Abstract
Sterol 14α-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity.
摘要
甾醇 14α-脱甲基酶（CYP51）是真核生物甾醇生物合成所必需的细胞色素 P450 酶，也是抗真菌唑类药物的治疗靶点。人们曾多次尝试将抗真菌药物重新用于治疗原生动物（原生动物门）引起的人类感染，但迄今为止，没有一种药物显示出足够的疗效。VNI 及其衍生物 VFV 是两种有效的原生动物门 CYP51 实验抑制剂，对恰加斯病、内脏利什曼病和昏睡病具有体内疗效，目前正在考虑作为抗原生动物候选药物。然而，VNI 对利什曼原虫和耐药型克氏锥虫的活性较低，而 VFV 的抗原生动物活性谱较宽，且代谢稳定性较差。在这项工作中，我们设计、合成并表征了一组类似物，并鉴定出两种新化合物（7 和 9），它们在抗原生动物活性、微粒体稳定性和药代动力学（特别是组织分布）方面均超过了 VNI/VFV，并且与 VNI/VFV 一样，没有急性毒性。
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