Small molecule mimetics of Humanin that normalize neuronal p-Akt as novel therapeutics for AD

护脑素小分子模拟物可使神经元 p-Akt 正常化，作为 AD 的新型疗法

• 批准号: 10211023
• 负责人: Varghese John
• 金额: $ 181.71万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10211023
• 关键词: Affect; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amino Acids; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Artificial Membranes; Binding; Binding Proteins; Biological; Biological Assay; Biological Availability; Brain; Cause of Death; Cell Membrane Permeability; Cell surface; Cells; Chemistry; Choline O-Acetyltransferase; Chondrocytes; Ciliary Neurotrophic Factor Receptor; Cognition; Complex; Critical Pathways; Data; Dementia; Development; Diabetes Mellitus; Disease; Docking; Dose; Drug Kinetics; Evaluation; Exposure to; Extracellular Domain; Genes; Genetic Transcription; Goals; Hippocampus (Brain); Human; IL6ST gene; Impaired cognition; In Vitro; Lead; Learning; Libraries; MK801; Membrane; Memory; Mitochondria; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neuronal Plasticity; Neurons; Oral; PI3 gene; Pathway interactions; Patients; Penetrance; Peptides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Population; Property; Protein Isoforms; Proteins; Receptor Signaling; Reporting; Risk Factors; Safety; Series; Signal Transduction; Site; Solubility; Stroke; Study models; Testing; Therapeutic; Tissues; Toxic effect; Traumatic Brain Injury; acetylcholine transporter; age related; aged; analog; apolipoprotein E-3; apolipoprotein E-4; base; brain tissue; cerebrovascular; data modeling; design; efficacy testing; high throughput screening; humanin; improved; in silico; in vivo; lead candidate; lead optimization; mimetics; mouse model; neuron loss; neuroprotection; neurotoxicity; novel strategies; novel therapeutic intervention; novel therapeutics; peptidomimetics; phosphoproteomics; postsynaptic; pre-clinical; preclinical development; prevent; receptor; response; screening; simulation; small molecule; therapeutic development

PROJECT SUMMARY/ABSTRACT Our recent discovery of orally brain permeable small molecules that mimic the bioactivity of Humanin (HN) peptide to enhance and normalize neuronal phospho-Akt (p-Akt) levels provides a unique opportunity for evaluating this new approach in Alzheimer's disease (AD). In this proposal, we will direct our efforts to optimize this new class of agents, focusing on screening additional hits, enhancing their potency, drug-like properties, solubility, oral brain permeability and efficacy in an AD model towards development of this novel therapeutic approach for AD. We will also use modeling to identify HN based peptidomimetics for testing. Our data show that these small molecule HN mimetics, like HN, can suppress neuronal death through its activation of the gp130 receptor and signaling via the PI3/Akt pathway and provide neuroprotection for primary hippocampal neurons against N-methyl D-aspartate (NMDA) and Aβ-induced neurotoxicity. HN is a naturally occurring mitochondrial-derived brain peptide that decreases with age and may act as a neuroprotective factor against AD-relevant neurotoxicity. Treatment of hippocampal neurons with our HN mimetic compound 2 resulted in an increase in p-Akt, and this correlated to its observed neuroprotective effects. In AD patients, a significant decrease in p-Akt has been reported. Similarly, in aged apolipoprotein E4 (ApoE4) mice, there is a significant decrease in p-Akt in the brain relative to age-matched ApoE3 mice suggesting that PI3/Akt signaling is affected by ApoE4, a risk factor in AD. Activation of PI3/Akt signaling can transcriptionally modulate genes related to memory such as choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) and may also regulate postsynaptic proteins involved in neuroplasticity. AD is the most prevalent age-related dementia, currently afflicting more than 5.4 million people in the US. Given the urgent need for new therapeutic approaches for AD, these HN mimetics could provide promising lead candidates for therapeutic development. In Aim 1, we plan to evaluate small molecule HN mimetics and peptidomimetics for activation of gp130 and normalization of p-Akt along with their neuroprotection against Aβ and NMDA induced neurotoxicity. In Aim 2, we would conduct a design and synthesis campaign using current SAR and new docking/modeling data to identify small mimetics, peptides and peptidomimetics. We will optimize potency, drug-like properties, solubility and oral brain bioavailability for efficacy testing. The best analogs/peptidomimetics from Aims 1 and 2 will undergo in vitro ADMET profiling and pharmacokinetic (PK) studies, along with phosphoproteomics analyses, in Aim 3 to prioritize the optimal compounds for in vivo efficacy testing in the ApoE4(TR):5XFAD murine model of AD as part of Aim 4. The goal is to identify orally available HN-mimetics that enhance/normalize brain p-Akt levels and improve cognition. Like HN itself, they could also have broader therapeutic applications in traumatic brain injury (TBI), stroke, Aβ-induced cerebrovascular dementia, amyotrophic lateral sclerosis (ALS) and could lead to a new class of preclinical candidates for AD.

项目摘要/摘要 我们最近发现了模仿人类生物活性（HN）的口服大脑可渗透的小分子 增强和标准化神经元磷酸化（P-AKT）水平的肽为独特的机会提供了独特的机会 评估阿尔茨海默氏病（AD）中的这种新方法。在此提案中，我们将把努力定向 优化这种新的代理商，专注于筛选额外的命中，增强其效力，类似毒品 AD模型中的特性，可溶性，口腔脑的渗透性和效率 AD的治疗方法。我们还将使用建模来识别基于HN的肽仪进行测试。我们的 数据表明，这些小分子HN模拟物（如HN）可以通过激活来抑制神经元死亡 通过PI3/AKT途径的GP130受体和信号传导，并为原发性提供神经保护 针对N-甲基D-天冬氨酸（NMDA）和Aβ诱导的神经毒性的海马神经元。 HN自然 发生线粒体衍生的脑胡椒，随着年龄的增长而降低，可能充当神经保护因子 反对与广告相关的神经毒性。用我们的HN模拟化合物2处理海马神经元2 导致P-AKT的增加，这与观察到的神经保护作用相关。在AD患者中 据报道，P-AKT的显着下降。同样，在老化的载脂蛋白E4（APOE4）小鼠中，有一个 相对于年龄匹配的APOE3小鼠，大脑的P-AKT显着降低，这表明PI3/AKT信号传导 受APOE4的影响，APOE4是AD的危险因素。 PI3/AKT信号的激活可以转录调节基因 与记忆有关的记忆，例如胆碱乙酰转移酶（CHAT）和囊泡乙酰胆碱转运蛋白（VACHT） 并可能调节与神经成形术有关的突触后蛋白。广告是最普遍的与年龄有关的 痴呆症目前在美国遭受超过540万人的困扰。考虑到迫切需要新的 这些HN模拟物的AD治疗方法可以为治疗提供有希望的铅候选者 发展。在AIM 1中，我们计划评估小分子HN模拟物和肽仪以激活 GP130和P-AKT的归一化及其针对Aβ和NMDA诱导的神经毒性的神经保护性。 在AIM 2中，我们将使用当前的SAR和新的对接/建模进行设计和合成活动 数据以识别小的模拟物，胡椒粉和辣妹。我们将优化效力，类似药物的特性， 溶解性和口服脑生物利用度以进行效率测试。 AIM 1和2的最佳类似物/肽仪 将接受体外ADMET分析和药代动力学（PK）研究，以及磷酸化蛋白质组学 分析，在AIM 3中，优先考虑APOE4（TR）中体内效率测试的最佳化合物：5XFAD 作为目标4的一部分，AD的鼠模型是确定口服可用的HN-Mimetics 提高/归一化脑P-AKT水平并改善认知。像HN本身一样，他们也可能更广泛 创伤性脑损伤（TBI），中风，Aβ诱导的脑血管痴呆的治疗应用， 肌萎缩性侧索硬化症（ALS）可能会导致一类新的AD临床前候选者。