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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该计划的重点是开发一类新型抗心律失常药物，可抑制病理性亢进的 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。综合征 – 儿茶酚胺能多形性室性心动过速 (CPVT) 是由以下原因引起的。 RyR2 过度活跃的功能获得性突变也与机制有关。在其他几种心律失常疾病中，但缺乏 RyR2 选择性抑制剂。这个跨学科项目的目标是根据抗心律失常临床候选者的选择发现天然产物verticilide（ent-verticilide）的对映体是一种有效的我们的初步数据是心肌细胞中 RyR2 介导的钙释放抑制剂。实验室包括发现 ent-verticilide 作为一种有效的（第一个）选择性抑制剂，与其镜像、自然形式相反，这些工具已经显示出抗心律失常的作用。 CPVT 疾病动物模型中的影响，从而支持选择性的前提初步结果还表明，治疗可以提高我们对 RyR2 生物学的理解。杀轮虫剂的从头化学合成提供了可再生的药物获取途径，以及快速类似物开发的平台，两者都支持药理学研究。 1 描述了探索 ent-verticilide 生物活性和药理学的更广泛计划，位于 RyR2，在心肌细胞和小鼠疾病模型中目标 2 的目标是准备分数。 ent-verticilide 类似物进一步优化效力，同时保留选择性。 ent-verticilide 是一个强大的先导产品，其模块化特性将有助于开发尽管缺乏 RyR2 的结构图，但结构-活性关系的分子图由于其规模和复杂性，这种方法的优势在于它能够适应环境的变化。 RyR2 结构生物学的最新技术，我们也将为此做出贡献（目标 1）。将在体内推进高效和选择性化合物的安全性和功效研究目标 3. 该项目本质上是高度协作和跨学科的，研究将推进一类以前从未用于治疗开发的新型化合物。结果已经增进了我们对 RyR2 分子药理学的理解，并有望改善人类健康的新型抗心律失常药物。