Pumilio: a novel target to control epilepsy

目前的抗癫痫药物对大约。三分之二的患者，并伴有严重的副作用。需要更好的药物，但缺乏新的药物靶点是一个重大障碍。我们使用果蝇（Drosophila melanogaster）的研究已经确定了一种名为Pumilio的蛋白质，它具有治疗癫痫的有利特性。Pumilio是所谓的“自我平衡机制”的一部分。这些机制被神经细胞用来调节它们的活动，以保持正常行为所需的水平。增加Pumilio水平在果蝇中具有强烈的抗惊厥作用。我们现在希望确定针对Pumilio的药物。我们已经进行了全面的药物筛选，并确定了阿伏苯宗，以增加Pumilio活动。正如预期的那样，阿伏苯宗对苍蝇有很强的抗惊厥作用。这是一个跨学科的研究项目，最初将合成阿伏苯宗的类似物，以产生具有更好药物特性（溶解性好，毒性低等）的活性化合物。将使用果蝇和斑马鱼癫痫发作模型测试合成的化合物的抗惊厥特性。有利的化合物将用于在啮齿动物全身性癫痫发作模型中进行测试。

Current antiepileptic drugs are effective for approx. two-thirds of patients and are associated with significant side-effects. Better drugs are needed, but a lack of novel drug targets is a significant barrier. Our research using the fruit fly (Drosophila melanogaster) has identified a protein called Pumilio, which has favourable properties to treat epilepsy. Pumilio is part of what is termed a 'homeostatic mechanism'. These mechanisms are used by nerve cells to regulate their activity in order to maintain a level that is appropriate for normal behaviour. Increasing Pumilio levels is strongly anticonvulsant in Drosophila. We now wish to identify drugs that target Pumilio. We have undertaken a comprehensive drug screen and have identified avobenzone to increase Pumilio activity. As might be expected, avobenzone is strongly anticonvulsant in flies. This is an interdisciplinary research project that will initially synthesize analogues of avobenzone to produce active compounds with better drug characteristics (good solubility, low toxicity etc.). Compounds synthesised will be tested for anticonvulsant properties using Drosophila and zebrafish seizure models. Favourable compounds will be taken forward for testing in rodent generalized seizure models.