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（来自授予的赠款申请） 阿尔茨海默氏病（AD）中能量稳态异常与突触功能障碍和 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AMP蛋白激酶（AMPK）的集成信号网络，该信号网络在流下运行 线粒体能量产生的作品，可以在AD中提供神经保护作用。部分抑制线粒体 复合物I（MCI）改善了葡萄糖的摄取和利用，树突状棘的成熟，长期潜在， 突触活动，认知功能并减少A和PTAU积累，氧化应激和炎症 导致AD和衰老的临床前小鼠模型中的神经保护作用。这些研究 建议改变线粒体能量稳态的新型策略可能具有深刻的翻译 AD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，我们开发了小分子，这些分子结合在黄素旁边 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 构成热量限制和运动引起的途径，包括激活AMPK；增加 抵抗氧化应激；线粒体生物发生，能量，动力学和功能增强； 糖原合酶激酶3活性的还原；脑衍生的神经营养因子（BDNF）的水平增加 和体内突触蛋白； A和PTAU和炎症的水平降低最终阻塞 AD小鼠的神经变性。团队在一系列系统（主要鼠标）中确认了这些效果 神经元，多种家庭AD的小鼠模型，喂养高脂饮食的野生型小鼠，按时间顺序老化 小鼠，线粒体从小鼠和人脑，人淋巴细胞，成纤维细胞和神经元细胞中分离出来 与人IPSC有所不同），支持这种方法的高转化潜力。优势 分子的能力包括渗透血脑屏障，低毒性，体内效率和 已知的分子靶标。基于目标验证和分子机制的鉴定，我们 开发了用于结构活性关系（SAR）研究的多个体外和体内测定 导致发展强大的发现漏斗和一系列新型专有化合物的阵列 具有有前途的毒品样特性的MCI抑制剂（已授予美国专利）。他们建议迈向小 通过在发现阶段输入BPN到诊所的分子疗法，其中BPN团队 顾问和CRO，我们将朝着确定临床前和发展候选人的识别， 并提交IND应用程序以准备I期临床试验。