Development of a Mirror-Image Natural Product as an Antiarrhythmic Therapeutic

开发镜像天然产物作为抗心律失常疗法

• 批准号: 10372134
• 负责人: Jeffrey Nicholas Johnston
• 金额: $ 77.71万
• 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: 2020-03-17 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372134
• 关键词: Accounting; Adult; Affinity; Animal Disease Models; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Binding; Biological; Biology; Calcium; Calorimetry; Cardiac; Cardiac Myocytes; Catecholaminergic Polymorphic Ventricular Tachycardia; Cell surface; Cessation of life; Clinical; Complex; Constitution; Critical Pathways; Cryoelectron Microscopy; Data; Depsipeptides; Development; Disease; Disease model; Docking; Dose; Drug Industry; Exhibits; Functional disorder; Generations; Goals; Health; Human; Human Genetics; Hyperactivity; Image; Implantable Defibrillators; In Vitro; Intracellular Membranes; Ion Channel; Ions; Laboratories; Lead; Measures; Mediating; Methylation; Molecular; Mus; Natural Products; Nature; Pathologic; Patients; Periodicity; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Property; Proteins; Public Health; Regulation; Research; Research Personnel; RyR2; Safety; Sarcoplasmic Reticulum; Side; Structure; Structure-Activity Relationship; Syndrome; Therapeutic; Tissues; Titrations; Toxic effect; Variant; Ventricular Arrhythmia; Work; analog; base; chemical synthesis; clinical candidate; clinical development; cost; crosslink; design; drug development; drug discovery; efficacy study; enantiomer; gain of function mutation; high risk; improved; in silico; in vivo; inhibitor; mortality; mouse model; novel; novel therapeutics; pre-clinical; preclinical development; programs; rare condition; response; safety study; small molecule; structural biology; success; sudden cardiac death; targeted treatment; therapeutic development; therapeutic target; tool; tool development

Project Summary This program focuses on the development of a new class of antiarrhythmic agents that inhibit pathologically hyperactive RyR2, the calcium release channel in the sarcoplasmic reticulum (intracellular) membrane. RyR2 is a validated therapeutic target in a human genetic arrhythmia syndrome – Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). CPVT is caused by gain of function mutations in RyR2. RyR2 hyperactivity has also been implicated mechanistically in several other arrhythmia disorders, but RyR2-selective inhibitors are lacking. The overarching goal of this transdisciplinary program is the selection of antiarrhythmic clinical candidates based on the discovery that the enantiomer of the natural product verticilide (ent-verticilide) is a potent inhibitor of RyR2-mediated calcium release in cardiomyocytes. Preliminary data from our laboratories includes the discovery of ent-verticilide as a potent and (the first) selective inhibitor, in contrast to its mirror-image, natural form. These tools have already shown an antiarrhythmic effect in CPVT animal models of disease, thereby supporting the premise that selective therapeutics can improve our understanding of RyR2 biology. Preliminary results are also founded upon a de novo chemical synthesis of verticilide that provides both renewable access to drug, as well as a platform for rapid analogue development, both in support of pharmacology studies. Aim 1 describes a broader program to explore ent-verticilide's biological activity and pharmacology, at RyR2, in cardiomyocytes, and in mouse models of disease. The goal of Aim 2 is to prepare scores of ent-verticilide analogues that further optimize potency while retaining selectivity. The premise is that ent-verticilide is a powerful lead whose modularity will enable the development of a molecular picture of structure-activity relationships despite the lack of a structural picture for RyR2 due to its size and complexity. A strength of this approach is its ability to adapt to changes in the state of the art in RyR2 structural biology, an effort to which we will contribute as well (Aim 1). Highly potent and selective compounds will be advanced in vivo for safety and efficacy studies in Aim 3. This program is highly collaborative and transdisciplinary in nature, and the studies will advance a novel class of compounds never-before-used in therapeutic development. Preliminary results have already advanced our understanding of RyR2 molecular pharmacology, and promise new antiarrhythmic agents to improve human health.

项目摘要 该计划的重点是开发一类新的抗肿瘤药物， 病理性过度活跃的RyR 2，肌浆网中的钙释放通道 （细胞内）膜。RyR 2是人类遗传性心律失常的有效治疗靶点 综合征-儿茶酚胺能多形性室性心动过速（CPVT）。CPVT由以下原因引起： 获得RyR 2的功能突变。RyR 2过度活跃也与 在其他几种心律失常疾病中，但缺乏RyR 2选择性抑制剂。总体 这一跨学科计划的目标是选择抗疟疾临床候选人的基础上， 基于天然产物轮枝环内酯（ent-verticilide）的对映体是一种有效的 心肌细胞中RyR 2介导的钙释放的抑制剂。我们的初步数据显示， 实验室包括发现了作为有效和（第一个）选择性抑制剂的恩替维昔酸， 与它的镜像，自然形态形成对比。这些工具已经显示出 在CPVT疾病动物模型中的作用，从而支持选择性 治疗方法可以提高我们对RyR 2生物学的理解。初步结果也发现 基于轮枝环内酯的从头化学合成，其提供了药物的可再生途径， 以及一个快速开发类似物的平台，两者都支持药理学研究。目的 1描述了一个更广泛的计划，探索ent-verticilide的生物活性和药理学，在 RyR 2，在心肌细胞和小鼠疾病模型中。目标2的目标是准备分数 对映-轮枝环内酯类似物，进一步优化效力，同时保持选择性。前提 恩替维他利是一种强有力先导物，其模块化将使得能够开发一种 尽管缺乏RyR 2的结构图，但结构-活性关系的分子图 因为它的尺寸和复杂性。这种方法的一个优点是它能够适应环境的变化， RyR 2结构生物学的最新技术，我们也将为此做出贡献（目标1）。 高效和选择性的化合物将在体内进行安全性和有效性研究， 目标3.该计划是高度合作和跨学科的性质，研究将 推进了一类以前从未用于治疗开发的新型化合物。初步 这些结果已经推进了我们对RyR 2分子药理学的理解， 改善人类健康的新型抗肿瘤药物。