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.

项目摘要 该计划的重点是开发一种抑制的新型抗心律失常剂 病理多动性RYR2，肌质网中的钙释放通道 （细胞内）膜。 RYR2是人类遗传心律不齐的经过验证的治疗靶标 综合征 - 儿茶酚胺能多态性的心室心动过速（CPVT）。 CPVT是由 RYR2中功能突变的增益。 RYR2多功能也已被机理暗示 在其他几种心律失常疾病中，但是缺乏RYR2选择性抑制剂。总体 该跨学科计划的目标是基于抗心律失常的临床候选者的选择 关于天然产品verticilide（ent-veridilide）的对映异构体是一种有效的发现 RYR2介导的心肌细胞中钙释放的抑制剂。来自我们的初步数据 实验室包括发现ent-verticilide是潜力和（第一个）选择性抑制剂， 与其镜像形式的自然形式相反。这些工具已经显示出一种抗心律失常 在CPVT疾病模型中的影响，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。也建立了初步结果 在从头开始的化学合成verticilide，既可以提供可再生的药物访问权限，as 作为快速模拟开发的平台，都支持药理学研究。目的 1描述了一个更广泛的计划，以探索ent-verticilide的生物学活动和药理学，at 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 在保持选择性的同时进一步优化效力的int-verticilide类似物的图像。前提 是ent-verticilide是一个强大的领导，其模块化将使一个人的发展 尽管缺乏RYR2的结构图片，但结构活性关系的分子图片 由于其大小和复杂性。这种方法的优势是它适应变化的能力 RYR2结构生物学中的艺术状态，我们也将为此做出贡献（AIM 1）。 高潜力和选择性化合物将在体内进行安全和效率研究。 AIM 3。该计划本质上是高度协作和跨学科的，研究将 推进一类新型的化合物，从未在热发育中使用。初步的 结果已经提高了我们对RYR2分子药理学的理解，并有望 新的抗心律失常药物可以改善人类健康。

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