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