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

项目摘要 该项目的重点是开发一种新型的抗心律失常药物 病理上高度活跃的RyR2，肌浆网中的钙释放通道 (细胞内)膜。RyR2是人类遗传性心律失常的有效治疗靶点 儿茶酚胺能多形性室性心动过速(CPVT)。CPVT是由以下原因引起的 RyR2功能突变的获得性。RyR2过度活动也与机制有关 在其他几种心律失常中，但缺乏RyR2选择性抑制剂。最重要的是 这一跨学科计划的目标是选择抗心律失常的临床候选对象 关于天然产物轮枝菌素(Et-verticilide)对映体的发现 RyR2介导的心肌细胞钙释放的抑制剂。来自我们的初步数据 实验室包括发现了恩替利特作为一种有效的(第一种)选择性抑制剂， 与它的镜像相反，自然的形式。这些工具已经显示出一种抗心律失常 在CPVT动物模型中的作用，从而支持选择性 治疗学可以提高我们对RyR2生物学的理解。初步结果也是成立的。 基于轮状内酯的从头化学合成，它提供了两种可再生的药物途径，如 也是一个快速开发模拟药物的平台，这两个平台都支持药理学研究。目标 1描述了探索Et-verticilide的生物活性和药理的更广泛的计划，请访问 RyR2，在心肌细胞和疾病的小鼠模型中。目标2的目标是准备分数 Et-verticilide类似物，在保持选择性的同时进一步优化效力。前提是 Ent-verticilide是一个强大的领导者，它的模块化将使 结构-活性关系的分子图，尽管缺乏RyR2的结构图 由于它的规模和复杂性。这种方法的一个优点是它能够适应 RyR2结构生物学的最新进展，我们也将为此做出贡献(目标1)。 高效力和高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.该项目本质上是高度协作和跨学科的，研究将 提出了一类在治疗开发中从未使用过的新型化合物。初步 这些结果已经促进了我们对RyR2分子药理学的理解，并承诺 改善人类健康的新型抗心律失常药物。

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.