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

从本质上讲，所有活细胞的细胞壁上都嵌入了类似通道的蛋白质。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渗透的。通道通常是细胞的关键组成部分，离子通道的打开和关闭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。离子通道也是由基因突变（如多发性硬化症）引起的一些异常过程的根源，或者具有对病原体生存能力至关重要的功能（如流感病毒）。由于这个原因，许多有用的药物通过强迫离子通道打开或关闭来起作用。具有这种功能的一类药物是金刚烷。它们结合并关闭了种类繁多的离子通道，包括流感病毒中名为M2的质子通道，以及在人类中被称为NMDA受体的神经元突触上发现的钙通道，NMDA受体与记忆和学习有关。由于这些原因，金刚烷既用于治疗流感感染，也用于减轻与帕金森病和阿尔茨海默病等疾病相关的神经变性症状。药物通常在一个特定的位置与蛋白质（如离子通道）特异性地相互作用，并且了解这些相互作用的精确物理性质可以促进设计更特异性，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，对NMDA受体的相同过程知之甚少。我们现在希望利用我们在M2案例中学到的知识，来了解与NMDA受体结合需要什么样的物理相互作用。此外，金刚烷类如金刚烷胺和美金刚胺是与NMDA受体结合的一类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。

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.