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.

项目总结/摘要 我们最近发现了模拟Humanin（HN）生物活性的口服脑渗透性小分子 肽增强和正常化神经元磷酸化Akt（p-Akt）水平提供了一个独特的机会， 评估这种治疗阿尔茨海默病（AD）的新方法。在本建议中，我们将努力 优化这类新的药物，重点是筛选额外的命中，提高其效力，药物样 性质、溶解度、口服脑渗透性和在AD模型中的功效，以开发这种新的 AD的治疗方法。我们还将使用建模来鉴定用于测试的基于HN的肽模拟物。我们 数据显示，这些小分子HN模拟物，如HN，可以通过其活化抑制神经元死亡， gp 130受体和信号转导通过PI 3/Akt途径，并提供神经保护的主要 海马神经元对N-甲基-D-天冬氨酸（NMDA）和Aβ诱导的神经毒性的保护作用。HN是一个自然 一种脑源性脑肽，随年龄增长而减少，可作为一种神经保护因子 抗AD相关神经毒性。用我们的HN模拟化合物2处理海马神经元 导致p-Akt增加，这与其观察到的神经保护作用相关。在AD患者中， 已经报道了p-Akt显著降低。同样，在老年载脂蛋白E4（ApoE 4）小鼠中， 相对于年龄匹配的ApoE 3小鼠，脑中p-Akt显著降低，表明PI 3/Akt信号传导 受AD风险因子ApoE 4影响。PI 3/Akt信号通路的激活可以转录调节基因 与记忆相关的如胆碱乙酰转移酶（ChAT）和囊泡乙酰胆碱转运蛋白（VAChT） 并且还可以调节涉及神经可塑性的突触后蛋白。AD是最常见的与年龄相关的 痴呆症，目前在美国有超过540万人受到影响。鉴于迫切需要新的 对于AD的治疗方法，这些HN模拟物可以提供有希望的用于治疗AD的先导候选物。 发展在目标1中，我们计划评估小分子HN模拟物和肽模拟物用于激活 gp 130和p-Akt沿着正常化以及它们对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 用于鉴定小模拟物、肽和肽模拟物的数据。我们将优化药效，药物性质， 溶解度和口服脑生物利用度用于功效测试。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，沿着磷酸蛋白质组学研究 分析，在目标3中优先考虑用于ApoE 4（TR）：5XFAD体内疗效试验的最佳化合物 AD的鼠模型作为目标4的一部分。目的是鉴定口服可利用的HN-模拟物， 增强/正常化脑p-Akt水平并改善认知。就像HN本身一样，他们也可以拥有更广泛的 在创伤性脑损伤（TBI）、中风、Aβ诱导的脑血管痴呆、 肌萎缩侧索硬化症（ALS），并可能导致一类新的临床前候选人的AD。