Dynamin Inhibitors as Tools for Dissecting the Endocytic Pathway in Neurons

动力抑制剂作为剖析神经元内吞途径的工具

• 批准号: nhmrc : 228406
• 负责人: Prof Adam Mccluskey
• 金额: $ 31.36万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/dynamin-inhibitors-tools-pathway-neurons/78510
• 关键词: Dynamin; Inhibitors; Tools; Dissecting; Endocytic

Nerve cells communicate by the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There is a finite number of vesicles, so they are recycled (endocytosis) for reuse. Some human neural diseases hijack the endocytic pathway for entry of pathological peptides, proteins or viruses to paralyse, kill or infect neurons. Our overall aim is to control nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy. At its most extreme, completely blocking endocytosis quickly results in a complete block in nerve communication. Therefore slowing it down (rather than blocking) might be a means to control some neural diseases. For example, a seizure is the uncontrolled firing of neurons. The main mechanisms controlling endocytosis converge on the protein dynamin. Dynamin can assemble into a tiny, tightly wound helix or spring. When energy (GTP hydrolysis) is applied to the nanospring it rapidly releases to cleave off empty recycling synaptic vesicles from the cell wall back into the neuron. Our premise is that blocking the nanospring may lead to a new generation of antiepileptic drugs. To achieve this we have already discovered the first chemical inhibitors of dynamin. In this project we will determine how they work, by showing that they target distinct sites in dynamin. We have embarked on an ambitious chemical synthesis program to greatly improve the potency and specificity of the inhibitors. We will expand this with an iterative approach using combinatorial chemistry. When applied to neurons, the drugs appear to be the first endocytosis inhibitors. Will test our proposal that they will reveal multiple points of action of dynamin in various stages of endocytosis. This project will prove the principle that the development of anti-dynamin drugs could lead to the first anti-endocytic drugs. This has the potential to lead to future development of targeted antiepileptic and anticancer drugs.

神经细胞通过释放神经递质进行交流，神经递质被包裹在神经末梢内的突触囊泡中。囊泡的数量有限，因此它们被循环利用（内吞作用）以重复使用。一些人类神经疾病通过劫持内吞途径，使病理性肽、蛋白质或病毒进入神经元，使神经元瘫痪、死亡或感染。我们的总体目标是控制神经交流，最终使我们能够治疗神经交流障碍，如癫痫。在最极端的情况下，完全阻断内吞作用会迅速导致神经通讯完全阻断。因此，减缓（而不是阻断）它可能是控制某些神经疾病的一种手段。例如，癫痫发作是神经元不受控制的放电。控制内吞作用的主要机制集中在蛋白质动力蛋白上。Dynamin可以组装成一个微小的、紧密缠绕的螺旋或弹簧。当能量（GTP水解）应用于纳米弹簧时，它迅速释放，从细胞壁上切割空的循环突触囊泡，回到神经元中。我们的前提是，阻断纳米弹簧可能会导致新一代抗癫痫药物的出现。为了实现这一目标，我们已经发现了动力蛋白的第一个化学抑制剂。在这个项目中，我们将确定它们是如何工作的，通过展示它们靶向dynamin中的不同位点。我们已经开始了一项雄心勃勃的化学合成计划，以大大提高抑制剂的效力和特异性。我们将用组合化学的迭代方法来扩展它。当应用于神经元时，这些药物似乎是第一个内吞抑制剂。将测试我们的建议，它们将揭示动力蛋白在内吞作用的各个阶段的多个作用点。该项目将证明抗动力蛋白药物的开发可能导致第一个抗内吞药物的原理。这有可能导致未来开发靶向抗癫痫和抗癌药物。