Mechanism of Inhibition of Viral and Neuronal Pore Loop Ion Channels by the Adamantanes

金刚烷类药物抑制病毒和神经元孔环离子通道的机制

• 批准号: G0901012/1
• 负责人: Jason Schnell
• 金额: $ 63.62万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901012%2F1
• 关键词: Mechanism; Inhibition; Viral; Neuronal; Pore

Essentially all living cells have channel-like proteins embedded in their cell walls. The presence of these channels selectively allow certain classes of charged molecules, or ions, to pass into or out of the cellular interiors, as cell walls by themselves are normally impermeable to such molecules. Channels are often critical components of cells, and opening and closing ion channels is at the centre of many normal cellular processes such as cell fate decisions or intercellular communication. Ion channels are also at the root of some abnormal processes that arise from genetic mutations such as multiple sclerosis, or have functions that are essential for pathogen viability such as in the influenza virus. For this reason, many useful drugs act by forcing ion channels to open or close. One family of drugs that function in this way are the adamantanes. They bind to, and close, a surprisingly wide variety of ion channels, including a proton channel in the flu virus called M2, and calcium channels that are found in humans at neuronal synapses called NMDA receptors, which are involved in memory and learning. For these reasons, adamantanes are prescribed both for the treatment of flu infections, and to alleviate the symptoms of neurodegeneration associated with diseases such as Parkinsons and Alzheimers. Drugs typically interact specifically with proteins such as ion channels at one particular site, and knowing the precise physical properties of those interactions can facilitate design of more specific, and therefore more effective or less toxic drugs. In previous work, we elucidated the physical location at which the adamantanes bind to the flu virus ion channel. Unfortunately, little is known about the same process in the NMDA receptor. We now hope to use what we learned in the M2 case, to understand what physical interactions are needed for binding to the NMDA receptors. In addition, adamantanes such as amantadine and memantine are part of a larger class of potentially therapeutic compounds that bind to the NMDA receptor. Thus, understanding the behaviour of the adamantanes may be broadly applicable for guiding development of more effective drug treatments for neurodegenerative diseases.

基本上所有的活细胞都有嵌入细胞壁的通道样蛋白。这些通道的存在选择性地允许某些类型的带电分子或离子进入或离开细胞内部，因为细胞壁本身通常对这些分子是不可渗透的。通道通常是细胞的关键组成部分，打开和关闭离子通道是许多正常细胞过程的中心，如细胞命运决定或细胞间通讯。离子通道也是一些异常过程的根源，这些异常过程是由遗传突变引起的，如多发性硬化症，或者具有对病原体生存能力至关重要的功能，如流感病毒。出于这个原因，许多有用的药物通过迫使离子通道打开或关闭来起作用。金刚烷类药物就是以这种方式发挥作用的一类药物。它们结合并关闭各种各样的离子通道，包括流感病毒中称为M2的质子通道，以及在人类神经元突触中发现的称为NMDA受体的钙通道，这些通道与记忆和学习有关。由于这些原因，金刚烷被规定用于治疗流感感染，并减轻与帕金森病和阿尔茨海默病等疾病相关的神经退行性疾病的症状。药物通常在一个特定位点与蛋白质（如离子通道）特异性相互作用，了解这些相互作用的精确物理性质可以促进更特异性的设计，因此更有效或毒性更小的药物。在以前的工作中，我们阐明了金刚烷与流感病毒离子通道结合的物理位置。不幸的是，人们对NMDA受体中的相同过程知之甚少。我们现在希望利用我们在M2案例中所学到的知识，了解与NMDA受体结合所需的物理相互作用。此外，金刚烷如金刚烷胺和美金刚是结合NMDA受体的较大类别的潜在治疗化合物的一部分。因此，了解金刚烷的行为可能广泛适用于指导开发更有效的神经退行性疾病药物治疗。