Targeting AbcA1 and Ldlr production for the Discoveryof Alzheimer's disease Drugs

阿尔茨海默病是最常见的无法治愈的痴呆症，影响5000万人 世界各地的个人。载脂蛋白E4（APOE 4）是最强的遗传风险因素，直接影响着 与其发病机制有关。ApoE是一种胆固醇和脂质载体蛋白， 老年痴呆症、衰老和其他神经系统疾病。对淀粉样蛋白的异构体依赖性作用 在人和小鼠中发现APOE 4的累积和清除是有害的。 ApoE 4和可能的ApoE 3的单倍不足减少淀粉样蛋白病理学。低密度 脂蛋白受体（LDLR）在ApoE蛋白的内吞中起重要作用。LDLR 已经发现过表达降低ApoE水平并抑制淀粉样蛋白形成。此外，本发明还 ApoE在脂质化中的作用影响阿尔茨海默病的发病机制。atp结合盒转运子A1 （AbcA 1）蛋白将细胞胆固醇转移到细胞外贫脂载脂蛋白上。 ABCA 1基因的过表达也被发现抑制淀粉样蛋白的形成。因此，我们设置 开发可以增加AbcA 1和/或Ldlr同时降低ApoE的小有机分子 蛋白质水平这些化合物可能会减少和清除淀粉样斑块沉积在受影响的 大脑并为阿尔茨海默病提供治疗益处。 五种三芳基甲基胺（TAMA）小分子被认为是降低ApoE的第一先导物 蛋白质水平（在人星形细胞瘤脑细胞系中减少>30%，使用ELISA分析）。的 TAMA药效团的作用机制是通过LXR拮抗作用。构效 相关性（SAR）研究的TAMA药效团在五个阶段的重点图书馆，确定 五个类药叔芳基磺酰胺和芳基胺作为新的先导化合物。他们不仅降低了ApoE水平 在体外，但也增加了AbcA 1/Ldlr蛋白水平验证的浓度依赖性研究。 纯R/S形式的三种手性先导化合物对ApoE和AbcA 1具有不成比例的影响， 多个目标的可能性。化合物127是8个先导化合物之一，它调节了细胞内的靶蛋白。 转基因小鼠大脑的初步体内研究。127的成功体内功效证实了其 通过血脑屏障（BBB）的能力。初步的体外毒理学实验显示， 8种先导化合物无毒。 SuRE的支持将使PI和他的本科生/研究生研究团队能够利用 在更新和更有效的磺胺先导化合物中鉴定出具有关键附件的TAMA药效团 来产生新的和新颖的基于支架的引线。这些支架预计会更轻，像药物一样， 化学和药物动力学稳定，且亲脂性较低。PI旨在进行化学合成 在一位坚定的顾问的指导下，在他的实验室里进行生物筛选。

Alzheimer’s disease is the most common incurable form of dementia affecting 50 million individuals worldwide. Apolipoprotein E4 (APOE4) is the strongest genetic risk factor that is directly linked to its pathogenesis. ApoE is a cholesterol- and lipid-carrier protein that has been implicated in Alzheimer’s disease, aging, and other neurological disorders. Isoform-dependent effect on amyloid accumulation and clearance have been found in humans and mice with APOE4 being detrimental. Haploinsufficiency of ApoE4 and possibly ApoE3 decreases amyloid pathology. Low Density Lipoprotein Receptor (LDLR) plays an important role in the endocytosis of ApoE proteins. LDLR overexpression has been found to decrease ApoE levels and inhibit amyloid formation. Additionally, ApoE’s role in lipidation influences Alzheimer’s pathogenesis. ATP-binding cassette transporter A1 (AbcA1) protein transfers cellular cholesterol onto extracellular lipid-poor apolipoproteins. Overexpression of ABCA1 gene has also been found to inhibit amyloid formation. Therefore, we set out to develop small organic molecules that can increase AbcA1 and/or Ldlr while decreasing ApoE protein levels. Such compounds would likely reduce and clear amyloid plaque deposition in affected brains and provide therapeutic benefit in Alzheimer’s disease. Five triarylmethyl amine (TAMA) small molecules emerged as first leads decreasing ApoE protein level (>30% reduction in the human astrocytoma brain cell line, analyzed using ELISA). The mechanism of action of the TAMA pharmacophore was via LXR antagonism. Structure-Activity Relationship (SAR) studies on the TAMA pharmacophore in five phases of focused libraries, identified five drug-like tertiaryl sulfonamides and aryl amines as new leads. They not only decreased ApoE levels in vitro, but also increased AbcA1/Ldlr protein levels validated by concentration-dependent studies. Three chiral leads in pure R/S forms had disproportionate effects on ApoE and AbcA1 raising the possibility of multiple targets. One of the 8 leads, compound 127 modulated the target proteins in the transgenic mice brains in preliminary in vivo studies. The successful in vivo efficacy of 127 validates its ability to pass the blood-brain barrier (BBB). Preliminary in vitro toxicological experiments revealed all the 8 lead compounds to be not toxic. The SuRE support will enable PI and his undergraduate/graduate research team to utilize the TAMA pharmacophore with critical appendages identified in newer and more potent sulfonamide leads to generate new and novel scaffolds-based leads. These scaffolds are expected to be lighter, drug-like, chemically and pharmacokinetically stable, and less lipophilic. PI aims at performing chemical synthesis and biological screening in his lab with the guidance of a committed consultant.