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

识别针对 IK 通道的抗心律失常药物的全谱理性方法

• 批准号: 10734513
• 负责人: IRA S COHEN
• 金额: $ 73.27万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734513
• 关键词: Action Potentials; Adrenergic Agonists; Affect; Agonist; Anti-Arrhythmia Agents; Antibiotics; Antihistamines; Arrhythmia; Atrial Fibrillation; Automobile Driving; Binding; Binding Sites; Biophysics; Calmodulin; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cell physiology; Computer software; Data; Docking; Dose; Dose Limiting; Drug Design; Drug Modelings; Drug Screening; Electrocardiogram; Electrophysiology (science); Enhancers; Event; Exposure to; FDA approved; Family; Female; Frequencies; Goals; Heart; Heart Atrium; Heart Diseases; Heart Rate; Human; In Vitro; Individual; Ion Channel; Lead; Ligand Binding; Long QT Syndrome; Measurement; Measures; Modeling; Molecular; Muscle Cells; Mutation; Pharmaceutical Preparations; Pharmacology; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphotransferases; Play; Potassium Channel; Process; Property; Proteins; Protocols documentation; Reporting; Research; Risk; Role; Safety; Signaling Molecule; Site; Specificity; Structure; Sudden Death; Syndrome; Testing; Therapeutic; Ventricular; Ventricular Arrhythmia; Voltage-Gated Potassium Channel; Work; biophysical properties; computer program; design; drug action; drug candidate; efficacy evaluation; fighting; in silico; inhibitor; insight; male; member; novel; novel therapeutics; pharmacologic; prevent; response; screening; sensor; side effect; small molecule libraries; success; targeted agent; voltage

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.

项目摘要 获得的长Q-T综合征（ALQTS）是心电图（EKG）的变化 心室电动事件，动作电位（AP）。这种延长的AP易于致命的心律不齐 和突然死亡。 ALQT是由FDA批准的许多药物诱导的。但是，批准的剂量是 受此副作用的限制。缓慢的延迟整流器IKS是一个K+电流，可以通过缩短来防止ALQT APD。该提案的重点是开发可以消除APD延长的候选代理商 由引起ALQT的药物诱导。有5个步骤调节通道的打开，电压传感器 激活，磷脂酰肌醇4,5-二磷酸（PIP2），钙调蛋白，ATP和孔的开放。两个 这些，电压传感器激活和PIP2结合，使我们获得了两种alqts的候选化合物。 由于许多候选药物因心脏毒性而失败，因此研究所有机制很重要 控制通道开放。第一个目标是AIM 1，调查了钙调蛋白和ATP的结合和毛孔 新型代理可以刺激开口以增加IK。选择的系统过程 这些新颖的药物被称为全光谱有理药物设计。通道的结构是 确定化合物修改特定步骤的化合物的绑定和结合位点确定 （例如，钙调蛋白和ATP相互作用以及孔口开口）。计算机程序使用此结构信息 筛选一个超过100万种化合物的化学库，最有可能结合到附近 结构定义的站点。多种化合物已经被确定为潜在有效的，并且 这些化合物为每个潜在位点提供了初步数据。 AIM 1测试这些化合物 确定他们对IK的作用以及剂量响应曲线和选择性。提出的机械 每个理论场所的研究将洞悉旨在靶向IK的任何抗心律失常药物。 第二目的AIM 2重点关注命中代理对离子频道功能和动作潜力的影响 犬室和心房心肌细胞。 AIM 1的每个最佳药物候选者都将在 IK的生物物理特性。他们还将研究各个浓度的动作电位， 刺激的频率，在两个对照条件下不存在和存在β激动剂的情况下， 延长APD为药物诱导ALQT的模型的人。包括心肌细胞，因为 铅化合物不得引起心房心律不齐作为安全性的测量。