Deconvolution of Physicochemical Properties Contributing to Passive Diffusion of Depsipeptides

有助于缩酚肽被动扩散的物理化学性质的反卷积

• 批准号: 10607589
• 负责人: Madelaine Paige Thorpe
• 金额: $ 3.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607589
• 关键词: Academic Medical Centers; Accounting; Adult; Affect; Amides; Anti-Arrhythmia Agents; Arrhythmia; Behavior; Biological; Biological Assay; Calcium; Calcium Channel; Cardiac Myocytes; Categories; Cell Membrane Permeability; Cell membrane; Cells; Cellular Membrane; Cessation of life; Characteristics; Chemicals; Collaborations; Coupled; Creativeness; Cyclodepsipeptides; Dantrolene; Data; Depsipeptides; Development; Diffusion; Disease; Drug Kinetics; Elements; Equilibrium; Esters; Exhibits; Extravasation; Feedback; Flecainide; Guidelines; Heart; Hydrogen Bonding; Individual; Laboratories; Lead; Longevity; Measures; Mediating; Methylation; Modification; Molecular Conformation; Molecular Weight; Mutation; Natural Products; Nature; Partition Coefficient; Patients; Penetration; Peptides; Periodicity; Permeability; Pharmaceutical Preparations; Positioning Attribute; Production; Property; Protein Isoforms; Public Health; Quality of life; Rationalization; Research; Route; RyR1; RyR3; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Scientist; Series; Solubility; Specificity; Structure; Structure-Activity Relationship; System; Testing; Tetracaine; Therapeutic; Toxic effect; Travel; United States; Variant; Ventricular Arrhythmia; Work; analog; design; efficacy study; enantiomer; falls; functional group; improved; in vivo; inhibitor; innovation; interest; lipophilicity; member; membrane activity; novel therapeutics; pharmacologic; pharmacophore; preservation; release of sequestered calcium ion into cytoplasm; single molecule; small molecule; small molecule therapeutics; stereochemistry; success; sudden cardiac death; tool

PROJECT SUMMARY Calcium in cardiomyocytes is released via an intracellular calcium channel, ryanodine receptor 2 (RyR2). In hearts where there are mutations in RyR2, spontaneous Ca2+ leakages can occur resulting in cardiac arrhythmias. Small molecule therapeutics such as flecainide, tetracaine, and dantrolene have low specificity, low membrane permeability, low solubility, poor selectivity, low potency, or toxicity. Therapeutic selectivity between RyR isoforms (RyR1, RyR2, RyR3) is lacking, heightening our interest in developing ent-verticilide as an anti- arrhythmic agent. This proposal focuses on the discovery and development of new therapeutics as antiarrhythmic agents. The proposed work is founded on our discovery of potent and selective inhibition of RyR2-mediated calcium flux by ent-verticilide. Through a cross-disciplinary collaboration, it was discovered that ent-verticilide is a selective inhibitor of RyR2-mediated calcium release, including a preliminary study of efficacy in vivo. As a 24 membered cyclic depsipeptide with a molecular weight of 853 Da, ent-verticilide falls outside of the category of a traditional small molecule drug. While “Beyond Rule of 5” compounds with in vivo activity are growing in number, an understanding of their pharmacokinetics (PK) has lagged, thereby requiring new chemical tools and creative tactics to advance the field. We will investigate the permeability of this unnatural product and its analogues by development of a structure-activity relationship profile focused on both permeability and increased efficacy. We aim to systematically design and synthesize structural analogues of ent-verticilide with varying degrees of N-methylation. Following the synthesis, we will study passive permeability and collect structural data to inform SAR, providing additional perspective for feedback to Specific Aim 1. By methodicalstructural change to ent-verticilide, we will create an SAR-based feedback loop between permeability, activity, structure, and conformation. A strength of this approach is the combination of rigorous tools to study passive membrane permeability, and cardiomyocyte-based functional studies using both permeabilized and non-permeabilized cells to achieve an overall hypothesis-driven approach to discover how analogues of ent-verticilide travel through cellular membranes and ultimately target RyR2. Another strength is our positioning to prepare diverse analogues that include ring-chain variants likely to exhibit contrasting permeability. With increased understanding of the mechanism of action, we hypothesize that we can design analogues of ent-verticilide with improved potency and selectivity, thereby providing a potential therapeutic against fatal ventricular arrhythmias.

项目总结 心肌细胞中的钙是通过细胞内钙通道兰尼定受体2(RyR2)释放的。在……里面 存在RyR2突变的心脏，可发生自发性钙泄漏，导致心脏 心律不齐。小分子疗法，如氟卡胺、丁卡因和丹曲林，特异性低， 膜渗透性低，溶解度低，选择性差，效力低，或毒性。治疗选择性在 RyR亚型(RyR1、RyR2、RyR3)的缺乏，增加了我们开发Ent-verticilide作为抗肿瘤药物的兴趣 心律失常剂。 这项建议的重点是发现和开发新的治疗方法作为抗心律失常的药物。这个 拟议的工作建立在我们发现通过以下途径有效和选择性地抑制RyR2介导的钙流动的基础上 Et-verticilde。通过一项跨学科的合作，人们发现ent-verticilide是一种选择性的 抑制RyR2介导的钙释放，包括体内疗效的初步研究。作为24个成员 环状去脂肽的相对分子质量为853 Da，对位轮状内酯属于传统的 小分子药物。在体内具有活性的“超越规则5”化合物数量不断增加的同时，一种 对它们的药代动力学(PK)的了解已经滞后，因此需要新的化学工具和创造性的 推进球场的战术。我们将研究这种非天然产品及其类似物的渗透性 结构-活性关系图谱的开发侧重于渗透性和增强的有效性。我们 目的系统地设计和合成不同程度的异构体结构类似物 N-甲基化。在综合之后，我们将研究被动渗透率并收集结构数据。 向SAR通报，为具体目标的反馈提供额外的视角1.通过方法论结构 更改为ent-verticilide，我们将在渗透率、活性、结构 和构象。这种方法的一个优点是结合了研究被动膜的严格工具。 通透性，以及使用通透性和非通透性细胞进行的基于心肌细胞的功能研究 实现一种总体假设驱动的方法，以发现ENT-Verticilde类似物如何通过 并最终以RyR2为靶点。另一个优势是我们的定位是准备各种类似物 这包括可能表现出反差渗透性的环链变体。随着对这一问题的理解不断加深 作用机制，我们假设我们可以设计出具有更好的药效和 选择性，从而提供了一种潜在的治疗致命的室性心律失常。