Glycosaminoglycan-Interacting Small Molecule (GISMO) as Alzheimer's Therapeutics

糖胺聚糖相互作用小分子（GISMO）作为阿尔茨海默病治疗剂 摘要 该项目的目的是开发一种新型的，改善疾病的口服治疗剂，用于治疗 老年痴呆症在该项目的第一阶段，我们通过专有技术鉴定了有前途的先导化合物， 糖胺聚糖相互作用小分子（GISMO）药物发现平台。GISMO基于 为阿尔茨海默病的病因提出了新的假说，并为阿尔茨海默病的治疗提供了新的原则。 治疗这种毁灭性的神经退行性疾病。老年痴呆症与 病理性聚集（即，淀粉样蛋白-β肽（Abeta肽）。根据GISMO 假设，Abeta聚集是必要的，但不足以引起阿尔茨海默病。相反，过度 积累和储存的一类复杂的多糖，糖胺聚糖（GAG），在 神经细胞的溶酶体是导致阿尔茨海默病的病理过程的另一个重要组成部分 疾病在我们目前的工作中，我们表明GISMO直接靶向硫酸乙酰肝素GAG（HS-GAG），抑制 A β 42与HS-GAG结合，并在与淀粉样变性相关的几种测定中具有有效的生物活性 在神经细胞培养中。具体地说，我们确定了GISMO先导化合物，抑制Abeta的摄取， 神经元细胞，并显示出针对Abeta肽Abeta 40和Abeta 42的有效神经保护特性。 这是Abeta/HS-GAG抑制剂（GISMO）具有有效的神经保护特性的首次报道， 有毒的Abeta肽除了减少神经细胞内淀粉样蛋白聚集物的毒性积累外， GISMOs还可以通过抑制淀粉样蛋白的扩散来减缓阿尔茨海默病的进展。 脑组织中的种子所鉴定的先导化合物符合Lipinski规则，并显示出选择性和其它性质。 药物性质。这些结果提供了体外靶点验证以及进一步研究的依据。 开发GISMO化合物作为阿尔茨海默病治疗剂。在具体目标1中，我们将评估 先导化合物的药代动力学特征、口服生物利用度、血脑屏障渗透性，以及 最大耐受剂量（MTD）。在具体目标2中，我们将测试两种最好的先导化合物 （选自目的1），以评价它们在两种AD转基因小鼠模型中的功效。我们将治疗转基因AD 用两种化合物以每种化合物的三种剂量给药小鼠，并使用 学习和记忆的标准测试，以及生物化学、组织病理学和免疫化学 方法.在具体目标3中，我们将对选定的开发候选药物进行进一步的临床前试验。 这些研究的成功完成将使我们能够选择临床前的开发候选者 开发，IND和临床试验。

Glycosaminoglycan-Interacting Small Molecule (GISMO) as Alzheimer's Therapeutics ABSTRACT The aim of this project is to develop a novel, disease-modifying oral therapeutic agent for the treatment of Alzheimer's Disease. In the first phase of this project, we identified promising lead compounds via proprietary Glycosaminoglycan-Interacting Small Molecule (GISMO) drug discovery platform. GISMOs are based on a novel hypothesis for the cause of Alzheimer's Disease and provide a new therapeutic principle for the treatment of this devastating neurodegenerative disease. Alzheimer's Disease is associated with the pathological aggregation (i.e., amyloidosis) of amyloid-beta peptides (Abeta peptides). According to GISMO hypothesis, Abeta aggregation is necessary but not sufficient to cause Alzheimer's Disease. Rather, excessive accumulation and storage of a class of complex polysaccharides, glycosaminoglycans (GAGs), in the lysosomes of nerve cells is another essential component of the pathological process leading to Alzheimer's Disease. In our current work we show that GISMOs directly target heparan sulfate GAGs (HS-GAGs), inhibit Abeta42 binding to HS-GAGs, and have potent biological activity in at several assays relevant to amyloidosis in nerve cell cultures. Specifically, we identified GISMO lead compounds that inhibit uptake of Abeta by neuronal cells, and display potent neuroprotective properties against Abeta peptides, Abeta40 and Abeta42. This is the first report of Abeta/HS-GAG inhibitors (GISMOs) having potent neuroprotective properties against toxic Abeta peptides. In addition to reducing the toxic accumulation of amyloid aggregates inside nerve cells, GISMOs may also slow the progression of Alzheimer’s disease by inhibiting the spread of amyloid proteopathic seeds in brain tissue. The identified lead compounds conform to Lipinski rules and display selectivity and other drug-like properties. These results provide in vitro target validation as well as justification for further development of GISMO compounds as Alzheimer's Disease therapeutics. In Specific Aim 1, we will assess the lead compounds for their pharmacokinetic profiles, oral bioavailability, blood-brain-barrier penetration, and establish their maximum tolerated dose (MTD). In Specific Aim 2, we will test the two best lead compounds (selected from Aim 1) for their efficacy in two transgenic mouse models of AD. We will treat transgenic AD mice with two compounds at three doses for each compound and evaluate the effectiveness of treatment using standard tests for learning and memory, as well as biochemical, histopathological, and immunochemical methods. In Specific Aim 3, we will perform further preclinical testing of the selected development candidate. The successful completion of these studies will allow us to select a development candidate for preclinical development, towards an IND, and clinical trials.