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

治疗阿尔茨海默病的糖胺多糖相互作用小分子(GISMO) 摘要 本项目的目的是开发一种新型的、能改善疾病的口服治疗剂，用于治疗 阿尔茨海默氏症。在这个项目的第一阶段，我们通过专利确定了有前景的先导化合物 糖胺多聚糖相互作用小分子(GISMO)药物发现平台。Gismo基于 阿尔茨海默病病因的新假说和治疗阿尔茨海默病的新原则 治疗这种毁灭性的神经退行性疾病。阿尔茨海默氏症与 淀粉样β蛋白多肽(Aβ多肽)的病理性聚集(即淀粉样变性)。根据Gismo的说法 假设，Aβ聚集是必要的，但不足以导致阿尔茨海默病。相反，过度了 一类复杂的多糖--糖胺多聚糖(GAG)的积累和储存 神经细胞的溶酶体是导致阿尔茨海默氏症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，我们证明了Gismos直接靶向硫酸乙酰肝素GAG(HS-GAG)，抑制 Abeta42与HS-GAG结合，并在几种与淀粉样变性相关的检测中具有强大的生物活性 在神经细胞培养中。具体地说，我们确定了Gismo先导化合物通过抑制Abeta的摄取 Abeta40和Abeta42对Abeta40和Abeta42具有强大的神经保护作用。 这是首次报道Abeta/HS-Gag抑制剂(Gismos)具有有效的神经保护作用。 有毒的Abeta多肽。除了减少神经细胞内淀粉样蛋白聚集体的有毒堆积外， Gismos还可能通过抑制淀粉样蛋白病症的扩散来减缓阿尔茨海默病的进展 脑组织中的种子。已鉴定的先导化合物符合利平斯基规则，并显示出选择性和其他 类似毒品的特性。这些结果提供了体外靶向验证以及进一步研究的理由 Gismo化合物作为阿尔茨海默病治疗药物的研究进展。在具体目标1中，我们将评估 先导化合物的药代动力学，口服生物利用度，血脑屏障穿透，以及 确定他们的最大耐受量(MTD)。在特定的目标2中，我们将测试两种最好的先导化合物 (选自AIM 1)在两个AD转基因小鼠模型上的疗效。我们将治疗转基因AD 给小鼠服用两种化合物，每种化合物三种剂量，并评估其治疗效果 学习和记忆的标准测试，以及生化、组织病理学和免疫化学 方法：研究方法。在具体目标3中，我们将对选定的开发候选者进行进一步的临床前测试。 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，走向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.