Glycosaminoglycan Interacting Small Molecules (GISMO) as Novel AD Therapeutics

描述(由申请人提供)：这项提案的目的是开发一种新的阿尔茨海默病(AD)疗法，通过迄今尚未探索的作用机制发挥作用。AD是美国第六大死因，目前尚无治愈方法。患者家属和照顾者的负担是巨大的，每年的护理成本接近1万亿美元。AD的过度菌株在很大程度上是由于缺乏有效的、创新的、可改变疾病的治疗方案。AD的一个突出的病理特征是神经元溶酶体途径的强烈激活，其内吞作用和自噬障碍与溶酶体细胞毒作用有关，是散发性AD的最早表现之一。此外，溶酶体储存功能障碍和糖胺多聚糖(GAG)如硫酸乙酰肝素(HS-GAG)的消化不良也是几种称为粘多糖病的神经退行性疾病的主要原因。HS-GAG与AD发病机制中的关键分子相互作用，即淀粉样蛋白(Abeta)、Tau和载脂蛋白E。我们的生物技术公司发现了一系列新的专利化合物，称为糖胺多糖相互作用小分子(Gismo)。这些分子通过一种独特的作用机制来抑制蛋白质与HS-GAG的相互作用，因此代表了治疗AD的一种新的治疗方法。这项建议的目标是开发一种新的AD治疗方法，通过内切酶途径抑制HS-Gag/Aβ蛋白聚集体的摄取。因此，Gismo化合物有望阻止溶酶体储存HS-GAG(与Abeta络合)，并保护神经细胞免受溶酶体功能障碍和细胞毒性的影响。此外，Gismo化合物还可以通过解离Abeta-Gag复合体，分散已经聚集的与GAG结合的Abeta，并减少细胞外Abeta的进一步积累。在这个项目中，具体目标1是评估24种已经确定的先导化合物的体外效力和安全性；具体目标2是进行铅优化以提高安全性和选择性；具体目标3是评估先导化合物的药代动力学特性以识别脑渗透化合物。这些研究的成功完成将导致确定三种优化的先导化合物，这些化合物将在AD的动物模型中进行体内测试，随后的目标是确定能够进行IND研究的临床前候选药物。

DESCRIPTION (provided by applicant): The aim of this proposal is to develop a novel class of Alzheimer's Disease (AD) therapeutics acting via a hitherto unexplored mechanism of action. AD is the sixth-leading cause of death in the United States with no known cure. The burden on families and caregivers of patients is immense, with the annual cost of care approaching $1 trillion. The exorbitant strain of AD arises, in large part, to the lack of effective, innovative ad disease-modifying treatment options. A prominent pathological feature of AD is a robust activation of the neuronal lysosomal pathway, endocytosis and autophagy - disturbances of which are associated with lysosomal cytotoxicity and represent one of the earliest manifestations in sporadic AD. Furthermore, dysfunction in lysosomal storage and indigestibility of glycosaminoglycans (GAGs) such as heparan sulfate GAGs (HS-GAGs) is also the primary cause of several neurodegenerative diseases known as mucopolysaccharidoses. HS-GAGs interact with key molecules implicated in AD pathogenesis, i.e., ¿-amyloid (Abeta), Tau and Apolipoprotein E. Our biotechnology company has discovered a new series of proprietary compounds called Glycosaminoglycan-Interacting Small Molecule (GISMO). These molecules work via a unique mechanism of action to inhibit protein interactions with HS-GAGs, and as such, represent a novel therapeutic approach for the treatment of AD. The goal of this proposal is to develop a novel AD therapeutic that inhibits uptake of HS-GAG/Abeta protein aggregates via endo-lysosomal route. Consequently, GISMO compounds are expected to prevent lysosomal storage of HS-GAGs (complexed with Abeta) and protect nerve cells against lysosomal dysfunction and cytotoxicity. Furthermore, GISMO compounds may also dissipate already aggregated Abeta bound to GAGs and reduce further accumulation of extracellular Abeta, by dissociating the Abeta-GAG complexes. During this project, Specific Aim 1 is to evaluate 24 already identified lead compounds for in vitro potency and safety; Specific Aim 2 is to perform lead optimization to improve safety and selectivity; and Specific Aim 3 is to assess pharmacokinetic properties of lead compounds to identify brain-penetrant compounds. The successful completion of these studies will result in identification of three optimized lead compounds that will be subjected to in vivo testing in animal models of AD, with the subsequent aim of identifying a Preclinical Candidate for IND-enabling studies.