Novel Analogs for Tauopathies and Their Mode of Action

项目摘要和摘要 阿尔茨海默病(AD)是一种进行性神经退行性疾病，被认为是主要原因 世界范围内的痴呆症。在美国，它是第六大死因。这会导致损失 记忆力、思维能力和任务表现。阿尔茨海默病的病理特征是淀粉样蛋白β积聚 (aβ)斑块和神经原纤维缠结(NFT)。研究表明，野生型tau的减少可以防止 一种β依赖的行为和认知缺陷，表明改变 牛磺酸可能是有益的。我们的实验室提供了令人信服的证据，要么使Sp1基因沉默，使用小分子 干扰RNA或用托芬那酸(TA)治疗动物可降低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是设计和合成新型衍生物的极佳候选者。因此，我们 使用先导化合物支架合成了一系列类似物，重点优化了效力，选择性， 并产生用于CNS传递的类药物分子，同时也磨练了 化合物。此外，我们的目标是减少这些化合物的COX相关作用，并增强它们的 靶向Sp1/tau。现在，我们有一系列的化合物，我们想要检查：功效，效力， 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。这个 该提案的目的如下：1)调查具有比TA更好的安全性的模拟的能力， 为了降低总tau、位点特异性tau磷酸化、CDK5、Sp1和COX2的mRNA和蛋白水平，在 体外模型，2)测试铅类似物的作用模式和目标接触，3)分析大脑 硅胶和体外方法中TA类似物的转移电势。预期的结果是，我们将 发现TA类似物通过螯合锌来特异性地靶向Sp1和其他相关生物标记物。我们也期待着 由于结构和理化特性，类似物将穿过血脑屏障(BBB) 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.