Development of Ryanodine Receptor 2 Selective Probes

Ryanodine 受体 2 选择性探针的开发

• 批准号: 9911333
• 负责人: Abigail Smith
• 金额: $ 3.02万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911333
• 关键词: Accounting; Adult; Animal Disease Models; Anti-Arrhythmia Agents; Arrhythmia; Attention; Biological Assay; Biology; Brain; Calcium; Calcium Channel; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Catecholaminergic Polymorphic Ventricular Tachycardia; Cessation of life; Chemicals; Clinic; Clinical; Collection; Coupling; Dantrolene; Data; Depsipeptides; Development; Disease; Drug Industry; Flecainide; Goals; Heart Diseases; Heart failure; Human; Image; Ion Channel; Laboratories; Lead; Mammals; Mediating; Mentors; Methods; Mutation; Myocardium; Natural Products; Nature; Patients; Periodicity; Pharmaceutical Preparations; Pharmacology Study; Physiological Processes; Play; Positioning Attribute; Property; Protein Isoforms; Public Health; Research; Role; RyR1; RyR3; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Side; Skeletal Muscle; Structure; Tetracaine; Therapeutic; Tissues; United States; Variant; Ventricular; Ventricular Arrhythmia; Work; analog; base; chemical synthesis; design; drug discovery; enantiomer; improved; in vivo; inhibitor/antagonist; innovation; novel; novel therapeutics; reduce symptoms; release of sequestered calcium ion into cytoplasm; screening; small molecule; small molecule therapeutics; structural heart disease; sudden cardiac death; therapeutic development; tool

PROJECT SUMMARY Ryanodine Receptor 2 (RyR2) mutations that result in dysregulated RyR2-mediated calcium release are associated with a variety of cardiovascular diseases. As a result, several small molecule probes have been used in the study and treatment of cardiac diseases through the targeting of RyR calcium channels. Flecainide, tetracaine, and dantrolene, the most common of these small molecule probes, are not without problems. Flecainide, for example, is contra-indicated in patients with structural heart defects or heart failure. Furthermore, selectivity of specific RyR isoforms (RyR1, RyR2, or RyR3) is rare, and to date, an RyR2-selective probe does not exist. New probes to selectively modulate RyR2 would be of great use both therapeutically and as tools to better understand the function of RyR2 and the mechanism of intracellular calcium flux. This proposal focuses on the development of a new class of antiarrhythmic agents using the hit compound discovered in the Johnston lab, ent-verticilide – the non-natural enantiomer of the natural product (–)-verticilide. This cyclic oligomeric depsipeptide is a potent and selective inhibitor of RyR2-mediated calcium release in mammals while the natural verticilide is inactive. We aim to use a structure-based design approach to help clarify the interaction of ent- verticilide with RyR2. This approach may lead to new findings in our search for potent, selective modulators of RyR2 for the treatment of cardiac disease. Our screening will be grounded first in the well-defined RyR2-mediated spontaneous calcium release assay. We aim to include both discrete collections of ring-size congeners and ‘unnatural’ enantiomers, two underexplored variables in natural-product based therapeutic development, to screen against the target (RyR2), potentially leading to new probes. We also propose to use ent-verticilide in pharmacological studies to determine ADME, while advancing the understanding of the mechanism of action and RyR2 function. Our approach is well suited towards the ultimate goals of both developing a potent, selective inhibitor of RyR2 as well as working towards defining the mechanism of action of ent-verticilide to treat cardiac arrythmias.

项目概要 Ryanodine 受体 2 (RyR2) 突变导致 RyR2 介导的失调 钙的释放与多种心血管疾病有关。 小分子探针已被用于心脏病的研究和治疗 RyR 钙通道的靶向作用最多。 例如，这些小分子探针的共同点并非没有问题。 结构性心脏缺陷或心力衰竭患者禁用。 特定 RyR 同工型（RyR1、RyR2 或 RyR3）的序列很少见，迄今为止，RyR2 选择性探针 不存在选择性调节 RyR2 的新探针。 治疗和作为更好地了解 RyR2 功能及其机制的工具 细胞内钙通量。 该提案的重点是开发一类新型抗心律失常药物，使用 约翰斯顿实验室发现的热门化合物，ent-verticilide——非天然对映体 这种环状寡聚缩肽是一种有效且具有选择性的天然产物 (–)-verticilide。 哺乳动物体内 RyR2 介导的钙释放抑制剂，而天然轮虫杀剂则无活性。 我们的目标是使用基于结构的设计方法来帮助阐明实体之间的交互 这种方法可能会在我们寻找有效的、 我们的筛选将是用于治疗心脏病的 RyR2 选择性调节剂。 我们的目标首先是基于明确的 RyR2 介导的自发钙释放测定。 包括环大小同系物和“非自然”对映体的离散集合，两个 基于天然产物的治疗开发中尚未充分探索的变量，以筛选 目标（RyR2），可能导致新的探针，我们还建议使用 ent-verticilide。 确定 ADME 的药理学研究，同时增进对 ADME 的理解 我们的方法非常适合最终的作用机制和 RyR2 功能。 开发一种有效的、选择性的 RyR2 抑制剂以及努力实现的目标 定义 ent-verticilide 治疗心律失常的作用机制。