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.

项目总结

项目成果

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

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