Novel Analogs for Tauopathies and Their Mode of Action

项目摘要和总结 阿尔茨海默病（Alzheimer's disease，AD）是一种进行性神经退行性疾病，被认为是阿尔茨海默病的主要病因 痴呆症患者的数量在美国，它是第六大死亡原因。它会导致 记忆力、思维能力和任务表现。AD的病理标志是β淀粉样蛋白的积累 （Aβ）斑块和神经纤维缠结（NFT）。研究表明，野生型tau蛋白的减少可以防止 Aβ依赖性行为和认知缺陷，这表明改变β依赖性行为和认知缺陷水平的治疗干预措施， tau可能是有益的。我们的实验室提供了令人信服的证据，无论是沉默Sp1基因，使用小 干扰RNA或用托芬那酸（TA）治疗动物，降低AD相关Sp1的表达 靶基因TA（Clotam® Rapid）目前在欧洲和其他国家用于治疗偏头痛症状 头痛TA作为一个很好的候选人的设计和合成的新衍生物。因此我们 合成了一系列类似物，使用先导化合物支架，通过重点优化效力，选择性， 并产生用于CNS递送的药物样分子，同时，也磨练了药物的物理性质。 化合物.此外，我们的目的是减少这些化合物的COX相关作用，并增强其 Sp1/tau的靶向。我们现在有一系列的化合物，我们想检验：功效，效力， 在体外细胞培养模型中的细胞毒性、潜在作用机制、选择性和脱靶效应。的 以下是该提案的目的：1）研究类似物的能力，其安全性比TA更好， 降低总tau蛋白、位点特异性tau蛋白磷酸化、CDK 5、Sp1和COX 2的mRNA和蛋白水平， 体外模型，2）测试铅类似物的作用模式和靶点接合，3）分析大脑 使用计算机模拟和体外方法测定TA类似物的转移潜力。预期的结果是，我们将 发现TA类似物通过螯合Zn特异性靶向Sp1和其他相关生物标志物。我们还预计， 由于结构和生理化学特征， 增强大脑渗透潜力。

Project Abstract and Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is considered the predominate cause of dementia worldwide. In the United States (US), it is the sixth leading cause of death. It results in a loss of memory, thinking skills and task performance. The pathological hallmarks of AD are accumulated amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs). Studies have shown that reduction in wild-type tau prevents Aβ-dependent behavioral and cognitive deficits, suggesting that therapeutic interventions that alter the levels of tau may be beneficial. Our lab provided convincing evidence that either silencing the Sp1 gene, using small interfering RNA, or treatment of animals with Tolfenamic Acid (TA), lowers the expression of AD-related Sp1 target genes. TA (Clotam® Rapid) is currently used in Europe and other countries to treat symptoms of migraine headaches. TA serves as an excellent candidate for the design and synthesis of novel derivatives. Thus, we synthesized a series of analogs using the lead compound scaffold by focusing on optimizing potency, selectivity, and generating drug-like molecules for CNS delivery, while, also, honing the physical properties of the compounds. Furthermore, we aimed to decrease the COX-related action of these compounds and enhance their targeting of Sp1/tau. We, now, have a series of compounds and we would like to examine: efficacy, potency, cytotoxicity, potential mechanism of action, selectivity and off target effects in an in vitro cell culture model. The following are the aims of the proposal: 1) Investigate the ability of analogs, with a better safety profile than TA, to lower the mRNA and protein levels of total tau, site specific tau phosphorylation, CDK5, Sp1, and COX2, in an in vitro model, 2) Testing of lead analogs for mode of action and target engagement, 3) Analyze the brain transfer potential of TA analogs using in silico and in vitro approaches. The expected outcomes are that we will find that TA analogs specifically target Sp1 and other related biomarkers by chelating Zn. We, also, expect that the analogs will cross the blood brain barrier (BBB) due to structural and physiochemical characteristics that enhance brain penetration potential.