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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：
10259755
负责人：
NATHAN N ALDER
金额：
$ 48.38万
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/10259755
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 lipidomics 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.

项目总结