Small Molecule Mitochondria-Targeted Therapeutics for AD (Supplement)

小分子线粒体靶向治疗 AD（补充）

• 批准号: 10621603
• 负责人: Eugenia Trushina
• 金额: $ 28.44万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621603
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Applications Grants; Award; Binding; Biochemistry; Biogenesis; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Caloric Restriction; Cell Count; Cell Differentiation process; Chronology; Clinic; Complex; Computational Biology; Coupled; Data; Dendritic Spines; Development; Ensure; Exercise; Fibroblasts; Flavin Mononucleotide; Functional disorder; Genus Hippocampus; Glycogen Synthase Kinase 3; Goals; Grant; High Fat Diet; Homeostasis; Human; In Vitro; Inflammation; Infrastructure; Laboratories; Legal patent; Long-Term Potentiation; Lymphocyte; Measures; Meta-Analysis; Mitochondria; Molecular; Molecular Target; Mus; Nerve Degeneration; Neurons; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase I Clinical Trials; Preparation; Production; Property; Protein Kinase; Proteins; Resistance; Series; Signal Transduction; Specificity; Stream; Structure-Activity Relationship; Synapses; System; Systems Biology; Toxic effect; Validation; Wild Type Mouse; aged; base; cognitive function; extracellular; familial Alzheimer disease; glucose uptake; improved; in vivo; induced pluripotent stem cell; inhibitor; mouse model; neuroprotection; novel; novel strategies; pre-clinical; preclinical development; small molecule; small molecule therapeutics; success; targeted treatment; translational potential; translational study; translational therapeutics

Project Summary/Abstract (from the awarded grant application) Abnormal energy homeostasis in Alzheimer’s Disease (AD) is associated with synaptic dysfunction and neurodegeneration. Emerging data generated using multiple systems biology approaches and meta-analysis in AD patients identified an AMP-protein kinase (AMPK) integrated signaling network that operates down stream of mitochondrial energy production and could provide neuroprotection in AD. Partial inhibition of mitochondrial complex I (MCI) improves glucose uptake and utilization, dendritic spine maturation, long-term potentiation, synaptic activity, cognitive function, and reduces A and pTau accumulation, oxidative stress and inflammation resulting in neuroprotection in pre- and symptomatic preclinical mouse models of AD and aging. These studies suggest that novel strategies to alter mitochondrial energy homeostasis may have profound translational therapeutic potential for AD. Using multiple biochemistry, computational and systems biology approaches, and extensive in vivo translational studies, we developed small molecules that bind next to the flavin mononucleotide redox center of MCI mildly inhibiting its activity. The molecular mechanism of MCI inhibitors impinges on pathways induced by caloric restriction and exercise including activation of AMPK; increased resistance to oxidative stress; enhanced mitochondrial biogenesis, energetics, dynamics and function; reduction of glycogen synthase kinase 3 activity; increased levels of brain-derived neurotrophic factor (BDNF) and synaptic proteins in vivo; a reduction in levels of A and pTau and inflammation ultimately blocking neurodegeneration in AD mice. The team confirmed these effects in a range of systems (primary mouse neurons, multiple mouse models of familial AD, wild-type mice fed with a high fat diet, chronologically aged mice, mitochondria isolated from mouse and human brain, human lymphocytes, fibroblasts and neuronal cells differentiated from human iPSCs), supporting the high translational potential of this approach. The advantages of the molecules include the ability to penetrate the blood brain barrier, low toxicity, in vivo efficacy, and the known molecular target. Based on the target validation and the identification of the molecular mechanism, we developed multiple in vitro and in vivo assays that were used for structure-activity relationship (SAR) studies resulting in the development of a robust Discovery Funnel and arrays of novel series of proprietary compounds MCI inhibitors with promising drug-like properties (US patent granted). They propose to advance small molecule therapeutics to the clinic by entering the BPN at the Discovery stage where, with the team of the BPN Consultants and CROs, we will progress toward the identification of preclinical and development candidates, and to the submission of the IND application in preparation for a Phase I Clinical Trial.

项目摘要/摘要（来自已授予的资助申请） 阿尔茨海默病（AD）中的异常能量稳态与突触功能障碍相关， 神经变性使用多种系统生物学方法和荟萃分析生成的新兴数据 AD患者确定了一个AMP-蛋白激酶（AMPK）整合的信号网络， 线粒体能量生产，并可以提供AD的神经保护。线粒体部分抑制 复合物I（MCI）改善葡萄糖摄取和利用，树突棘成熟，长时程增强， 突触活动，认知功能，并减少A β和pTau积累，氧化应激和炎症 导致AD和衰老的临床前和症状前小鼠模型中的神经保护。这些研究 这表明改变线粒体能量稳态的新策略可能具有深远的翻译意义， AD的治疗潜力。使用多种生物化学，计算和系统生物学方法， 通过广泛的体内翻译研究，我们开发出了与黄素相邻的小分子， MCI的单核苷酸氧化还原中心轻度抑制其活性。MCI抑制剂的分子机制 影响热量限制和运动诱导的途径，包括AMPK的激活;增加 增强线粒体生物发生、能量学、动力学和功能; 糖原合成酶激酶3 β活性降低;脑源性神经营养因子（BDNF）水平升高 和突触蛋白; A β和pTau水平的降低和炎症最终阻断 AD小鼠的神经变性。研究小组在一系列系统中证实了这些效应（初级小鼠）。 神经元，家族性AD的多种小鼠模型，用高脂肪饮食喂养的野生型小鼠，按时间顺序老化 小鼠、从小鼠和人脑分离的线粒体、人淋巴细胞、成纤维细胞和神经元细胞 从人iPSC分化而来），支持了这种方法的高翻译潜力。优点 这些分子的优点包括穿透血脑屏障的能力、低毒性、体内功效以及 已知分子靶点。在靶点验证和分子机制鉴定的基础上， 开发了多种用于结构-活性关系（SAR）研究的体外和体内测定方法 导致了一个强大的发现漏斗和专利化合物系列的发展 MCI抑制剂具有有希望的药物样特性（美国专利授予）。他们建议小规模推进 在发现阶段进入BPN，与BPN的团队一起， 顾问和CRO，我们将朝着确定临床前和开发候选人的方向发展， 以及提交IND申请以准备I期临床试验。