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

靶向 AbcA1 和 Ldlr 的产生以发现阿尔茨海默病药物

• 批准号: 10797916
• 负责人: Santanu Maitra
• 金额: $ 9.95万
• 依托单位: CALIFORNIA STATE UNIVERSITY FRESNO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797916
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Affect; Aging; Alzheimer' s Disease; Amines; Amyloid; Apolipoprotein E; Apolipoproteins; Astrocytoma; Biological; Blood - brain barrier anatomy; Brain; Carrier Proteins; Cell Line; Chemicals; Cholesterol; Dementia; Deposition; Drug Kinetics; Endocytosis; Enzyme-Linked Immunosorbent Assay; Genes; Human; In Vitro; Individual; Lead; Libraries; Link; Lipids; Low Density Lipoprotein Receptor; Mus; Pathogenesis; Pharmaceutical Preparations; Phase; Play; Production; Protein Isoforms; Proteins; Research; Role; Senile Plaques; Structure-Activity Relationship; Students; Sulfonamides; Therapeutic; Toxicology; Training; Transgenic Mice; amyloid formation; amyloid pathology; antagonist; apolipoprotein E-3; apolipoprotein E-4; appendage; brain cell; career; chemical synthesis; experimental study; extracellular; genetic risk factor; higher education; in vivo; lipophilicity; nervous system disorder; novel; overexpression; pharmacophore; recruit; replication factor C; scaffold; screening; small molecule; undergraduate student

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.

阿尔茨海默病是最常见的无法治愈的痴呆症，影响着 5000 万人 世界各地的个人。载脂蛋白 E4 (APOE4) 是最强的遗传风险因素，直接影响 与其发病机制有关。 ApoE 是一种胆固醇和脂质载体蛋白，与 阿尔茨海默病、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 已发现 APOE4 在人类和小鼠体内的积累和清除是有害的。 ApoE4 和可能的 ApoE3 的单倍体不足会降低淀粉样蛋白病理学。低密度 脂蛋白受体 (LDLR) 在 ApoE 蛋白的内吞作用中发挥重要作用。低密度脂蛋白受体 已发现过度表达可降低 ApoE 水平并抑制淀粉样蛋白形成。此外， ApoE 在脂化中的作用影响阿尔茨海默病的发病机制。 ATP 结合盒转运蛋白 A1 (AbcA1) 蛋白将细胞胆固醇转移到细胞外的贫脂载脂蛋白上。 研究还发现 ABCA1 基因的过度表达可以抑制淀粉样蛋白的形成。因此，我们设置 致力于开发可增加 AbcA1 和/或 Ldlr 同时减少 ApoE 的有机小分子 蛋白质水平。这些化合物可能会减少和清除受影响的淀粉样斑块沉积 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) 小分子成为降低 ApoE 的第一线索 蛋白质水平（人星形细胞瘤脑细胞系减少>30%，使用 ELISA 分析）。这 TAMA 药效团的作用机制是通过 LXR 拮抗作用。结构-活性 重点库的五个阶段中 TAMA 药效团的关系 (SAR) 研究，确定 五种类似药物的叔芳基磺酰胺和芳基胺作为新的先导化合物。它们不仅降低了 ApoE 水平 在体外，还增加了经浓度依赖性研究验证的 AbcA1/Ldlr 蛋白水平。 纯 R/S 形式的三个手性先导对 ApoE 和 AbcA1 具有不成比例的影响，从而提高了 多个目标的可能性。 8 个先导化合物之一，化合物 127 调节了 转基因小鼠大脑的初步体内研究。 127的成功体内功效验证了其 通过血脑屏障（BBB）的能力。初步体外毒理学实验揭示了所有 8种铅化合物无毒。 SuRE 的支持将使 PI 及其本科生/研究生研究团队能够利用 在更新、更有效的磺酰胺先导化合物中鉴定出具有关键附属物的 TAMA 药效团 产生新的、新颖的基于支架的线索。这些支架预计会更轻，像药物一样， 化学和药代动力学稳定，亲脂性较低。 PI旨在进行化学合成 在一位忠诚的顾问的指导下，在他的实验室进行生物筛查。