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: 10589858
• 负责人: Jeffrey Nicholas Johnston
• 金额: $ 76.88万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589858
• 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; Constitutional; Critical Pathways; Cryoelectron Microscopy; Data; Depsipeptides; Development; Disease; Disease model; Docking; Dose; Drug Industry; Endowment; Exhibits; Functional disorder; Generations; Goals; Health; Human; Human Genetics; Hyperactivity; Image; Implantable Defibrillators; In Vitro; Ion Channel; Ions; Laboratories; Lead; Measures; Mediating; Membrane; 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; Structure; Structure-Activity Relationship; Syndrome; Therapeutic; Tissues; Titrations; Toxic effect; Variant; Ventricular Arrhythmia; Work; analog; candidate selection; 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; pharmacologic; pre-clinical; preclinical development; programs; rare condition; response; safety study; small molecule; structural biology; structural determinants; 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）。 CPVT 是由 RyR2 的功能获得突变。 RyR2 过度活跃也与机制有关 在其他几种心律失常疾病中，但缺乏 RyR2 选择性抑制剂。首要的 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 心肌细胞中 RyR2 介导的钙释放抑制剂。我们的初步数据 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， 与其镜像的自然形式形成鲜明对比。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 治疗可以提高我们对 RyR2 生物学的理解。初步结果也成立 基于杀轮虫剂的从头化学合成，它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。目的 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。前提 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。这种方法的优点是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 开发出一类以前从未用于治疗开发的新型化合物。初步的 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。

项目成果

ent -Verticilide B1 inhibits type 2 ryanodine receptor channels and is antiarrhythmic in Casq2-/- mice.

ent -Verticilide B1 抑制 2 型兰尼定受体通道，并在 Casq2-/- 小鼠中具有抗心律失常作用。

• DOI: 10.1101/2023.07.03.547578
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Gochman,Aaron;Do,TriQ;Kim,Kyungsoo;Schwarz,JacobA;Thorpe,MadelaineP;Blackwell,DanielJ;Smith,AbigailN;Akers,WendellS;Cornea,RazvanL;Laver,DerekR;Johnston,JeffreyN;Knollmann,BjornC
• 通讯作者: Knollmann,BjornC

Structure-Activity Relationships for the N-Me- Versus N-H-Amide Modification to Macrocyclic ent-Verticilide Antiarrhythmics.

N-Me- 与 N-H-酰胺修饰对大环 ent-Verticilide 抗心律失常药的结构-活性关系。

• DOI: 10.1021/acsmedchemlett.2c00377
• 发表时间: 2022
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: Smith,AbigailN;Thorpe,MadelaineP;Blackwell,DanielJ;Batiste,SuzanneM;Hopkins,CoreyR;Schley,NathanD;Knollmann,BjornC;Johnston,JeffreyN
• 通讯作者: Johnston,JeffreyN