Pumilio: a novel target to control epilepsy

Pumilio：控制癫痫的新靶点

• 批准号: 1927490
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1927490
• 关键词: Pumilio; novel; target; control; epilepsy

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.

目前的抗癫痫药物大约有效。三分之二的患者，并与显著的副作用有关。需要更好的药物，但缺乏新的药物靶点是一个重大障碍。我们对果蝇(黑腹果蝇)的研究发现了一种名为Pumilio的蛋白质，它具有治疗癫痫的良好特性。Pumilio是所谓的“自我平衡机制”的一部分。神经细胞使用这些机制来调节自己的活动，以维持适合正常行为的水平。在果蝇中，增加Pumilio水平是很强的抗惊厥作用。我们现在希望确定针对普米利奥的药物。我们已经进行了一项全面的药物筛查，并确定了阿维苯宗可以增加浮选活性。不出所料，阿沃苯宗对果蝇有很强的抗惊厥作用。这是一个跨学科的研究项目，最初将合成阿维苯宗的类似物，以生产具有更好的药物特性(良好的溶解性，低毒等)的活性化合物。合成的化合物将用果蝇和斑马鱼癫痫模型测试抗惊厥特性。有利的化合物将在啮齿动物全身性癫痫模型中进行测试。