Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections.
Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections.
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DOI：
10.1371/journal.pntd.0004772
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发表时间：
2016-06
影响因子：
3.8
通讯作者：
Unnasch TR
中科院分区：
文献类型：
--
作者：
Mhashilkar AS;Vankayala SL;Liu C;Kearns F;Mehrotra P;Tzertzinis G;Palli SR;Woodcock HL;Unnasch TR
蜕皮激素受体的同源物先前已在人类丝虫寄生虫中鉴定。由于在脊椎动物中未发现蜕皮激素受体，因此它及其控制的调节途径代表了有吸引力的潜在化疗靶点。20-羟基蜕皮激素对感染B的沙鼠的给药。马来感染性幼虫破坏了它们向成虫阶段寄生虫的发育。建立了掺入B的稳定哺乳动物细胞系。在HEK 293细胞中的马来蜕皮激素受体配体结合结构域，其异二聚体伴侣和分泌的荧光素酶报告基因。这是用来筛选一系列的蜕皮激素激动剂，确定七个激动剂在亚微摩尔浓度的活性。A B。Malayi蜕皮激素受体配体结合域被开发并用于研究这些激动剂的配体-受体相互作用。观察到虚拟筛选结果与筛选测定之间的良好相关性。基于这两种方法，甾体蜕皮激素激动剂和化合物的二酰肼家族被鉴定为潜在受体激动剂的丰富来源。在建模和筛选结果的进一步确认中，预测为强蜕皮激素激动剂的两种化合物Ponasterone A和Muristerone A刺激微丝蚴和未成熟阶段从成虫寄生虫中排出。这些研究证实了B的潜力。Malayi蜕皮激素受体作为药物靶点，并提供了一种快速评价化合物的方法，用于开发一类新的抗人类丝虫寄生虫的药物。人类丝虫寄生虫是两种被忽视的热带疾病的病原体，国际社会的目标是消除这些疾病。目前的消除方案依赖于有限数量药物的大规模分发，一旦出现耐药性，这些方案就有可能失败。因此，迫切需要新的化学治疗剂来补充目前的武器库。丝虫是一种蜕皮动物，其发育过程受蜕皮激素受体的控制。在这里，我们验证了丝虫蜕皮激素受体作为化疗靶点的潜力，并报告了可用于靶向化合物的高通量和虚拟筛选试验的发展。
A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites. The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites. The human filarial parasites are the causative agents of two neglected tropical diseases targeted for elimination by the international community. The current elimination programs rely upon the mass distribution of a limited number of drugs, leaving the programs open to failure in the event that resistance develops. Thus, there is a critical need for novel chemotherapeutic agents to supplement the current arsenal. The filarial parasites are ecdysozoans, whose developmental processes are controlled by a master regulator, the ecdysone receptor. Here we validate the potential of the filarial ecdysone receptor as a chemotherapeutic target and report the development of high throughput and virtual screening assays that may be used to compounds that target it.