First-in-class peptide therapeutics for mitochondrial disorders: molecular mechanism of action and optimization of design

线粒体疾病的一流肽疗法：分子作用机制和设计优化

基本信息

批准号：
10058469
负责人：
NATHAN N ALDER
金额：
$ 53.37万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10058469
关键词：
Address Affect Aging Alzheimer&apos s Disease Animal Diseases Behavior Binding Bioenergetics Biological Assay Biological Availability Biomimetics Biophysics Calcium Calorimetry Cardiolipins Cations Cell Culture Techniques Cell Line Cell Survival Cell model Cell physiology Chronic Clinical Trials Complex Confocal Microscopy Coupled Crista ampullaris Diabetes Mellitus Disease Electrostatics Energy Metabolism Equilibrium Evaluation FDA approved Fluorescence Foundations Free Radical Scavenging Gene Expression Goals Health Heart Diseases Heritability Inner mitochondrial membrane Interdisciplinary Study Ions Kidney Diseases Kinetics Label Lead Libraries Lipid Bilayers Lipids Lipoproteins Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Medicine Membrane Membrane Structure and Function Metabolic Diseases Mitochondria Mitochondrial Diseases Modeling Molecular Molecular Analysis Molecular Conformation Molecular Mechanisms of Action Morphology Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Organelles Outcome Oxidative Phosphorylation Oxidative Stress Pathologic Pathology Pattern Peptide Conformation Peptides Permeability Phase Physiologic pulse Play Polymers Process Production Property Proteins Reactive Oxygen Species Research Research Support Resolution Role Safety Sampling Series Shotguns Side Site Solid Stress Structure Surface System Techniques Testing Therapeutic Thermodynamics Treatment Efficacy Variant Work Yeasts base biophysical analysis biophysical techniques crosslink design functional restoration improved insight interdisciplinary approach interfacial islet amyloid polypeptide membrane assembly membrane model mitochondrial dysfunction mitochondrial membrane molecular dynamics nanodisk next generation peptide analog peptide drug physical property preclinical trial preservation protein complex protein expression protein transport stressor virtual

项目摘要

PROJECT SUMMARY Mitochondria are organelles that play a dominant role in energy metabolism and many other cellular processes. Mitochondrial dysfunction is associated with primary heritable diseases and aging-related declines in health, including chronic pathologies like cancer, diabetes and neurodegeneration. There are currently no cures for mitochondrial diseases. However, Szeto-Schiller (SS) peptides have emerged among the most promising therapeutics for promoting mitochondrial health. As shown by preclinical and clinical trials, and as exemplified by the lead compound SS-31 (Elamipretide), SS peptides show exceptionally broad therapeutic efficacy in treating mitochondrial dysfunction. Using a multidisciplinary approach, our research team has conducted the first in-depth analysis of the molecular mechanism of action (MoA) of SS peptides. Our work supports a unique mechanism in which SS peptides interact with cardiolipin-rich mitochondrial membranes and modulate general physical membrane properties, thereby underpinning their broad therapeutic potential. The objective of the proposed project is twofold. The first goal is to thoroughly understand the MoA of SS peptides. To this end, we will leverage our solid foundation of mechanistic insights to test, refine, and expand our working models using computational, reductionist, mitochondrial, and cellular systems. The second goal is to identify the physicochemical properties of SS peptides that are most critical to their mechanism. To this end, we will evaluate a series of rationally designed SS peptide constructs with variations in the tetrapeptide cationic/aromatic motif, using our established functional assays. With our highly interdisciplinary research team, we will approach these goals as three separate aims. First, we will address how SS peptides interact with lipid bilayers and modulate their physical properties using a combination of computational and biophysical approaches with biomimetic model membrane systems. This will render critical information on equilibrium peptide binding models, high resolution structural information on peptide conformational dynamics and interaction with lipid groups, and how peptides modulate membrane electrostatics, lipid structural dynamics, and bilayer polymorphic changes. Second, we will evaluate the effects of SS peptides on the structure and function of membranes from yeast and mammalian models. This will establish the sites of peptide interaction in the morphologically complex mitochondrion, how peptides affect the stability and assembly of membrane complexes, the distribution of lipids within mitochondria, and lipid turnover kinetics. Finally, using mitochondrial and cellular models, we will analyze the mechanisms by which SS peptides restore function under pathological conditions including oxidative stress, high calcium load, and amyloidogenic proteins involved in type II diabetes and Alzheimer’s disease. By this multi-tiered approach, our results will yield unprecedented insights into the mechanism of this class of therapeutics with particular relevance to aging-related diseases. Further, our peptide screen will inform the design of SS peptide variants with greater efficacy and/or bioavailability.

项目概要线粒体是在能量代谢和许多其他细胞中起主导作用的细胞器线粒体功能障碍与原发性遗传性疾病和衰老相关的衰退有关。在健康方面，包括癌症、糖尿病和神经退行性疾病等慢性疾病，目前还没有。然而，司徒席勒 (SS) 肽已成为治疗线粒体疾病的最有效方法之一。促进线粒体健康的疗法如临床前和临床试验所示。以先导化合物 SS-31（Elamipretide）为例，SS 肽显示出异常广泛的治疗作用我们的研究团队采用多学科方法，取得了治疗线粒体功能障碍的功效。我们的工作首次对 SS 肽的分子作用机制 (MoA) 进行了深入分析。支持一种独特的机制，其中 SS 肽与富含心磷脂的线粒体膜相互作用，调节一般物理膜特性，从而支撑其广泛的治疗潜力。该项目的目标有两个：第一个目标是彻底了解 SS 肽的 MoA。为此，我们将利用我们坚实的机械洞察力基础来测试、完善和扩展我们的使用计算、还原论、线粒体和细胞系统的工作模型。确定对其作用机制最关键的 SS 肽的理化特性。我们将评估一系列合理设计的具有四肽变化的 SS 肽构建体阳离子/芳香基序，使用我们已建立的功能测定法以及我们高度跨学科的研究。团队，我们将把这些目标作为三个独立的目标来实现，首先，我们将解决 SS 肽如何相互作用。与脂质双层并结合计算和生物物理来调节其物理特性仿生模型膜系统的方法这将提供有关平衡的关键信息。肽结合模型、肽构象动力学的高分辨率结构信息和与脂质基团的相互作用，以及肽如何调节膜静电、脂质结构动力学、其次，我们将评估SS肽对结构和双层多态性的影响。酵母和哺乳动物模型的膜的功能这将建立肽相互作用的位点。形态复杂的线粒体，肽如何影响膜的稳定性和组装复合物、线粒体内脂质的分布以及脂质周转动力学最后，使用线粒体。和细胞模型，我们将分析SS肽在病理条件下恢复功能的机制包括与 II 型糖尿病有关的氧化应激、高钙负荷和淀粉样蛋白生成等病症通过这种多层次的方法，我们的结果将产生前所未有的见解。此类疗法的机制与衰老相关疾病特别相关。肽筛选将为设计具有更高功效和/或生物利用度的 SS 肽变体提供信息。