The Structural Basis of Antiarrhythmic Drug Binding in Voltage-gated Ion Channels

电压门控离子通道中抗心律失常药物结合的结构基础

• 批准号: 10558582
• 负责人: MICHAEL J LENAEUS
• 金额: $ 16.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558582
• 关键词: Affect; American; Anti-Arrhythmia Agents; Area; Arrhythmia; Binding; Biological Models; Calcium Channel; Calcium Channel Blockers; Cardiac; Chemistry; Chimera organism; Clinical; Complex; Coupling; Cryoelectron Microscopy; Crystallization; Data; Dedications; Development; Diltiazem; Disease; Drug Binding Site; Drug Prescriptions; Drug Side Effects; Electrolytes; Electrophysiology (science); Flecainide; Future; Gene Mutation; Goals; Health Expenditures; Heart; Heart Atrium; Heart Diseases; Human; Inherited; Ion Channel; Ion Channel Gating; Lidocaine; Mentors; Methods; Modeling; Molecular; Molecular Mechanisms of Action; Morbidity - disease rate; Myocardium; Nature; Nervous System Physiology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiology; Proteins; Research; Resolution; Safety; Site; Sodium Channel; Sodium Channel Blockers; Structural Models; Structure; Techniques; Testing; Ventricular Arrhythmia; Visualization; Work; X-Ray Crystallography; clinically relevant; design; drug action; drug development; experimental study; human disease; improved; insight; mortality; novel; novel therapeutics; protein complex; success; therapeutically effective; voltage

Abstract/Project Summary Cardiac arrhythmias affect millions of Americans and are a common cause of morbidity and mortality in older Americans, as well as health care expenditures. They have many causes including inherited gene mutations, electrolyte disturbances, and drug side effects—though all of these causes share the misfiring of voltage-gated ion channels in myocardium. Anti-arrhythmic drugs (AAD) are widely used to treat both atrial and ventricular arrhythmias by blocking such channels, though there is currently a limited understanding of the AAD molecular mechanism of action on a structural level. In this proposal, I aim to study AADs in model voltage-gated sodium and calcium channels, using the widely used sodium channel blocker AAD lidocaine and flecainide as well as the widely used calcium channel blocker AAD diltiazem. I will use established techniques of electrophysiology and X-ray crystallography to study AAD in complex with bacterial voltage-gated sodium and calcium channels, while working to establish new structural models of the AAD binding site using concatenated bacterial channels, higher order channels, and Cryo-EM methods. I expect these experiments to allow for a better understanding of voltage-gated ion channel physiology and aid in the design of safer and more effective AAD, as well as novel therapeutics that may be used for treatment of atrial and ventricular arrhythmias.

摘要/项目摘要 心律失常影响着数百万美国人，是一个常见原因 美国老年人的发病率和死亡率以及医疗保健 支出。它们有很多原因，包括遗传基因突变， 电解质紊乱和药物副作用——尽管所有这些原因都有一个共同点 心肌中电压门控离子通道的失火。抗心律失常 药物（AAD）广泛用于治疗房性和室性心律失常 封锁此类渠道，尽管目前对此的了解有限 AAD 在结构水平上的分子作用机制。在这个提案中，我的目标是 研究电压门控钠通道和钙通道模型中的 AAD，使用 广泛使用的钠通道阻滞剂 AAD 利多卡因和氟卡尼以及 广泛使用的钙通道阻滞剂AAD地尔硫卓。我将使用已建立的 电生理学和 X 射线晶体学技术研究 AAD 与细菌电压门控钠通道和钙通道形成复合物，同时 致力于建立 AAD 结合位点的新结构模型 连接细菌通道、高阶通道和冷冻电镜方法。我 期望这些实验能够更好地理解电压门控离子 通道生理学并有助于设计更安全、更有效的 AAD 作为可用于治疗心房和心室疾病的新型疗法 心律失常。