MANIPULATING IKS AS A THERAPEUTIC APPROACH TO CARDIAC ARRHYTHMIAS

操纵 IKS 作为心律失常的治疗方法

基本信息

批准号：
8978576
负责人：
Jianmin Cui
金额：
$ 79.64万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8978576
关键词：
Action Potentials Adverse effects Animals Arrhythmia Binding Binding Sites Canis familiaris Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cavia Cells Characteristics Clinical Clinical Trials Computational algorithm Computer Simulation Computer software Computing Methodologies Coupling Databases Dependence Disease Docking Doctor of Philosophy Drug Industry Equilibrium FDA approved Face Goals Heart Human Ion Channel Ions Kinetics Laboratories Lead Long QT Syndrome Marketing Measures Membrane Modeling Molecular Movement Muscle Cells Mutation Normal tissue morphology Outcome Pathologic Patients Pharmaceutical Preparations Phosphatidylinositol 4,5-Diphosphate Physiological Preclinical Drug Evaluation Probability Process Proteins Risk Role Safety Site Sodium Specificity Structural Models Structure Sudden Death Syndrome Testing Therapeutic Time Tissues Torsades de Pointes Ventricular Ventricular Arrhythmia Work Xenopus oocyte base cost drug candidate drug development drug discovery facsimile improved innovation novel public health relevance research study screening sensor small molecule voltage

项目摘要

DESCRIPTION (provided by applicant): This project proposes a straightforward approach to rational drug screening for ion channel-based diseases. The basic function of ion channels is to provide membrane current. In a tissue with the expression of many types of ion channels, a pathologic change in one type of channel may cause diseases. Our approach hypothesizes that the normal tissue function can be restored by compensating for the change in net current from any of the channels produced by the cell; all that is required is that a reasonable facsimile of normal net current flow be restored. We propose to apply this approach to Long Q-T Syndrome (LQTS), a condition that can cause a ventricular arrhythmia (torsades de pointe) that can lead to sudden death. The duration of the ventricular action potential (APD) depends on the balance of outward and inward currents flowing at plateau potentials. The outward currents include the delayed rectifiers IKr and IKs, while the inward currents include persistent sodium current (INaP). Specific mutations in any of these channel proteins that cause a reduction in outward current or increase in inward current are associated with congenital long QT syndrome (LQTS). There is also a much more prevalent problem called acquired LQTS (aLQTS) that is most often associated with off target effects of drugs and therefore cost the pharmaceutical industry billions of dollars and even removes from the market some compounds that could have effectively treated other diseases. To this end, we will use recent structural information concerning IKs channel activation for in silico drug screening to search for compounds with the highest probability of interacting with the IKs channel. We will apply the candidate compounds to freshly isolated guinea pig and canine cardiac ventricular myocytes to determine their effects on the ventricular action potential and the underlying ion currents in both control and LQTS conditions. The compounds that have the most favorable changes in the LQTS APD would be identified as viable candidate compounds. Our screening databases will include more than 1,500 FDA-approved small molecule drugs. If any of these FDA-approved drugs work as an IKs-enhancing compound, it should face smaller safety barriers for FDA approval. Our approach will be built on novel structural sites in the IKs channel identified by our recent work and innovative computer algorithms for molecular docking. The significance of our approach is both specific and general. Specifically if successful, candidate compounds for both congenital and acquired forms of LQTS will emerge, permitting those afflicted with the congenital form to avoid the dangers of sudden death, while allowing existing drugs or drug candidates (previous excluded for this side effect) to be made safer for clinical use. At present the various ion channels in tissues have been identified and their physiological roles defined, the structure and structure basis of function of variety of ion channels have been elucidated, and powerful computational methods have been developed. Therefore, more generally, if successful, this approach can point the way in defining how a combination of experimental studies and computer simulations can lead to rational drug development for other ion channel diseases. This new paradigm will help ion channel-targeting drug discovery be "faster, cheaper, and safer" and will reduce the use of animals.

描述（由申请人提供）：该项目提出了一种针对基于离子通道的疾病的合理药物筛选的简单方法。离子通道的基本功能是在表达多种离子通道的组织中提供膜电流。我们的方法爱好者认为，可以通过补偿细胞产生的任何通道的净电流的变化来恢复正常的组织功能；所需要的只是合理的模拟。普通的我们建议将此方法应用于长 Q-T 综合征 (LQTS)，这种情况会导致室性心律失常（尖端扭转型室性心动过速），从而导致猝死。取决于在平台电位流动的向外和向内电流的平衡，向外电流包括延迟整流器IKr和IKs，而持续向内电流包括钠电流。 (INaP)。导致外向电流减少或内向电流增加的任何通道蛋白的特定突变都与先天性长 QT 综合征 (LQTS) 有关。还有一种更为普遍的问题，称为获得性 LQTS (aLQTS)。最常与药物的脱靶效应相关，因此给制药业带来了数十亿美元的损失为此，我们将使用有关 IK 通道激活的最新结构信息进行计算机药物筛选，以寻找与 IK 相互作用的可能性最高的化合物。我们将候选化合物应用于新鲜分离的豚鼠和犬心室肌细胞，以确定它们在对照和 LQTS 条件下对心室动作电位和潜在离子电流的影响。 LQTS APD 中的药物将被确定为可行的候选化合物，我们的筛选数据库将包括 1,500 多种 FDA 批准的小分子药物，如果这些 FDA 批准的药物中的任何一种作为 IK 增强化合物发挥作用，那么它应该面临较小的安全障碍。 FDA 的批准。我们的方法将建立在我们最近的工作和创新的分子对接计算机算法确定的 IK 通道中的新颖结构位点上，如果成功的话，我们的方法对于先天性候选化合物来说具有特殊意义和一般意义。 LQTS 的后天性和后天性形式将会出现，使患有先天性 LQTS 的患者避免猝死的危险，同时允许现有药物或候选药物（之前因这种副作用而被排除）目前，组织中的各种离子通道已被识别，其生理学定义的作用已被阐明，各种离子通道的结构和功能的结构基础已被阐明，并且已开发出强大的计算方法。更广泛地说，如果成功，这种方法可以为定义如何结合实验研究和计算机模拟来导致其他离子通道疾病的合理药物开发指明道路，这种新范例将有助于离子通道靶向药物的发现“更快、更快速”。更便宜、更安全”减少动物的使用。