A full spectrum rational approach to identify antiarrhythmic agents targeting IKs Channels

项目摘要 获得性长Q-T综合征(ALQTS)是由于心电图(EKG)延长而引起的一种改变。 室电事件，动作电位(AP)。这种延长的AP易导致致命性心律失常。 和猝死。ALQTS是由FDA批准的许多药物引起的。然而，批准的剂量为 受到这种副作用的限制。慢速延迟整流器IKS是一种K+电流，它可以通过短路来防止LQTS 警察局。该方案的重点是开发能够消除动作电位时程延长的候选药物。 由导致aLQTS的药物引起。有5个步骤来调节通道的开度，电压传感器 激活，磷脂酰肌醇，4，5-二磷酸(PIP2)，钙调蛋白，三磷酸腺苷和毛孔的开放。其中两个 这些，电压传感器激活和PIP2结合，使我们找到了两个候选化合物作为aLQTS。 由于许多候选药物是由于心脏毒性而失败的，所以研究所有的机制是很重要的。 控制通道打开。第一个目标，目标1，研究钙调蛋白和三磷酸腺苷如何结合和穿孔 新的试剂可以刺激开放，以增加iKs。选拔的系统化过程 这些新型药物的实现被称为全光谱合理药物设计。该通道的结构是 研究并确定了化合物在通道开放中修饰特定步骤的结合部位 (例如，钙调素和三磷酸腺苷的相互作用和孔道开放)。计算机程序使用这种结构信息 为了筛选100多万种化合物的化学库，寻找那些最有可能结合在 结构上定义的站点。多种化合物已经被确定为潜在有效的和 从这些化合物中提供了每个潜在位置的初步数据。AIM 1测试这些化合物以 确定它们对iKs的作用，以及它们的剂量反应曲线和选择性。拟议的机械论 对每个治疗部位的研究将为任何针对iKs的抗心律失常药物提供洞察力。这个 第二个目标，目标2，重点是刺激剂对离子通道功能和动作电位的影响。 犬心室肌和心房肌细胞。来自目标1的每一种最佳候选药物将在 IKs的生物物理性质。他们还将被研究在多种浓度下的动作电位， 刺激频率，以及在两种对照条件下没有和存在β激动剂，以及 那些延长apd作为药物诱导的aLQT模型的研究。包括心房肌细胞是因为 铅化合物不得引起房性心律失常作为安全措施。

Project Summary Acquired Long Q-T Syndrome (aLQTS) is a change in the electrocardiogram (EKG) due to lengthening of the ventricular electrical event, the action potential (AP). This lengthened AP predisposes to a lethal arrhythmia and sudden death. aLQTS is induced by many drugs approved by the FDA. However, the approved doses are limited by this side effect. The slow delayed rectifier, IKs, is a K+ current that can prevent aLQTS by shortening the APD. This proposal focuses on developing candidate agents that can eliminate the APD prolongation induced by drugs that cause aLQTS. There are 5 steps that regulate opening of the channel, voltage sensor activation, phosphatidylinositol 4,5-biphosphate (PIP2), Calmodulin, ATP and opening of the pore. Two of these, voltage sensor activation and PIP2 binding, have led us to two candidate compounds for aLQTS. Because many drug candidates fail due to cardiac toxicity, it is important to investigate all mechanisms controlling channel opening. The first aim, Aim 1, investigates how calmodulin and ATP binding and pore opening can be stimulated by novel agents to increase IKs. The systematic process by which the selection of these novel agents is achieved is called Full Spectrum Rational Drug Design. The structure of the channel is studied and the binding sites for compounds to modify particular steps in channel opening are determined (e.g., calmodulin and ATP interactions and pore opening). A computer program uses this structural information to screen a chemical library of more than 1 million compounds for those most likely to bind near to the structurally defined site. Multiple compounds have already been identified as potentially effective and preliminary data are provided from these compounds for each potential site. Aim 1 tests these compounds to determine their action on IKs, as well as their dose response curve and selectivity. The proposed mechanistic studies of each therapeutic site will provide insight into any antiarrhythmic drug designed to target IKs. The second aim, Aim 2, focuses on the effects of the hit agents on the ion channel’s function and action potential in canine ventricular and atrial myocytes. Each optimal drug candidate from Aim 1 will be studied on the biophysical properties of IKs. They will also be studied on the action potential at multiple concentrations, frequencies of stimulation, and in the absence and presence of a β agonist in both control conditions, and those that prolong the APD as a model for drug induced aLQTs. Atrial myocytes are included because the lead compound must not cause atrial arrhythmias as a measurement for safety.