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.

项目概要/摘要 我们最近发现了模仿护脑素 (HN) 生物活性的口服脑渗透性小分子 增强和正常化神经元磷酸化 Akt (p-Akt) 水平的肽为 评估这种治疗阿尔茨海默病 (AD) 的新方法 在本提案中，我们将努力： 优化这类新型药物，重点是筛选额外的命中，增强其效力，类似药物 AD 模型中的特性、溶解度、口腔脑渗透性和功效，以开发这种新型药物 我们还将使用模型来识别基于 HN 的肽模拟物以进行测试。 数据表明，这些小分子 HN 模拟物，如 HN，可以通过其激活来抑制神经死亡 gp130 受体和通过 PI3/Akt 途径的信号传导，并为原发性神经元提供神经保护 海马神经元对抗 ​​N-甲基 D-天冬氨酸 (NMDA) 和 Aβ 诱导的 HN 是一种天然的神经毒性。 线粒体衍生的脑肽随着年龄的增长而减少，可能充当神经保护因子 用我们的 HN 模拟化合物 2 治疗海马神经元。 导致 p-Akt 增加，这与其在 AD 患者中观察到的神经保护作用相关。 据报道，p-Akt 显着降低，在老年载脂蛋白 E4 (ApoE4) 小鼠中，p-Akt 显着降低。 与年龄匹配的 ApoE3 小鼠相比，大脑中 p-Akt 显着降低，表明 PI3/Akt 信号传导 受 ApoE4 的影响，ApoE4 是 AD 的危险因素，PI3/Akt 信号传导的激活可以转录调节基因。 与记忆有关的如胆碱乙酰转移酶（ChAT）和囊泡乙酰胆碱转运蛋白（VAChT） 还可能调节参与神经可塑性的突触后蛋白，AD 是最常见的与年龄相关的疾病。 鉴于迫切需要新的治疗方法，目前美国有超过 540 万人患有痴呆症。 AD 的治疗方法，这些 HN 模拟物可以为治疗提供有希望的主要候选药物 在目标 1 中，我们计划评估小分子 HN 模拟物和肽模拟物的激活作用。 gp130 和 p-Akt 正常化及其针对 Aβ 和 NMDA 诱导的神经毒性的神经保护作用。 在目标 2 中，我们将使用当前的 SAR 和新的对接/建模进行设计和综合活动 数据来识别小模拟物、肽和肽模拟物，我们将优化效力、类似药物的特性， 用于功效测试的溶解度和口服脑生物利用度。来自目标 1 和 2 的最佳类似物/肽模拟物。 将进行体外 ADMET 分析和药代动力学 (PK) 研究以及磷酸蛋白质组学 分析，在目标 3 中优先考虑 ApoE4(TR):5XFAD 体内功效测试的最佳化合物 AD 小鼠模型作为目标 4 的一部分。目标是确定口服可用的 HN 模拟物 增强/正常化大脑 p-Akt 水平并改善认知能力，就像 HN 本身一样，它们也可以具有更广泛的功能。 在创伤性脑损伤 (TBI)、中风、Aβ 诱导的脑血管痴呆中的治疗应用 肌萎缩侧索硬化症 (ALS) 可能会导致一类新的 AD 临床前候选药物。