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(来自获奖拨款申请) 阿尔茨海默病(AD)能量平衡异常与突触功能障碍和 神经退行性变。使用多种系统生物学方法和荟萃分析生成的新兴数据 AD患者发现了一个向下游运行的AMP-蛋白激酶(AMPK)整合信号网络 对线粒体能量产生的影响，并可在AD中提供神经保护。线粒体部分抑制 复合体I(MCI)可促进葡萄糖的吸收和利用，树突棘成熟，长时程增强， 突触活动，认知功能，减少A和Ptau的积累，氧化应激和炎症 从而在AD和衰老的前期和症状性临床前小鼠模型中发挥神经保护作用。这些研究 提示改变线粒体能量动态平衡的新策略可能具有深刻的翻译 阿尔茨海默病的治疗潜力。使用多种生物化学、计算和系统生物学方法，以及 广泛的体内翻译研究，我们开发了结合在黄素旁边的小分子 MCI的单核苷酸氧化还原中心对其活性有轻度抑制作用。MCI抑制剂的分子机制 卡路里限制和运动对包括激活AMPK在内的通路的影响；增加 抗氧化性；增强线粒体的生物发生、能量学、动力学和功能； 糖原合成酶3活性降低；脑源性神经营养因子水平升高 和体内的突触蛋白；A和PTAU水平的降低和炎症最终阻止 阿尔茨海默病小鼠的神经变性。研究小组在一系列系统(初级鼠标)中证实了这些影响 神经元，多种家族性AD小鼠模型，高脂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、成纤维细胞和神经细胞 与人类IPSCs不同)，支持这种方法的高翻译潜力。优势 包括穿透血脑屏障的能力、低毒、体内疗效和 已知的分子目标。在靶点验证和分子机制确定的基础上，我们对其进行了初步研究 发展了多种体外和体内试验，用于构效关系(SAR)研究 结果开发了一个强大的发现漏斗和一系列新的专利化合物 具有前景看好的类药物特性的MCI抑制剂(获得美国专利)。他们提议小笔垫付。 分子治疗学通过进入BPN的发现阶段来到临床，在那里，BPN的团队 顾问和CRO，我们将在确定临床前和开发候选人方面取得进展， 并提交IND申请，为I期临床试验做准备。