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: 10412623
• 负责人: Santanu Maitra
• 金额: $ 13.97万
• 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/10412623
• 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; Future; Genes; Goals; Grant; Human; In Vitro; Individual; Laboratories; Lead; Libraries; Link; Lipids; Low Density Lipoprotein Receptor; Modification; Mus; Pathogenesis; Pharmaceutical Preparations; Phase; Play; Process; Production; Protein Isoforms; Proteins; Research; Role; Senile Plaques; Structure-Activity Relationship; Student recruitment; Students; Sulfonamides; Therapeutic; Toxicology; Training; Transgenic Mice; Underrepresented Students; Western Blotting; amyloid formation; amyloid pathology; analog; antagonist; apolipoprotein E-3; apolipoprotein E-4; appendage; base; brain cell; career; chemical synthesis; experimental study; extracellular; genetic risk factor; higher education; in vivo; lipophilicity; medical schools; molecular mass; 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)是最强的直接致病基因 与其发病机制有关。载脂蛋白E是一种胆固醇和脂质载体蛋白，已被认为与 阿尔茨海默氏症、衰老和其他神经疾病。淀粉样蛋白的异构体依赖效应 已经在人类和小鼠体内发现了APOE4的蓄积和清除，APOE4是有害的。 ApoE4和ApoE3的单倍体不足可降低淀粉样蛋白的病理改变。低密度 脂蛋白受体(LDLR)在载脂蛋白E的内吞作用中起着重要作用。LDLR 已发现过度表达可降低载脂蛋白E水平并抑制淀粉样蛋白的形成。另外， 载脂蛋白E在脂化中的作用影响阿尔茨海默病的发病机制。三磷酸腺苷结合盒运输器A1 (ABCA1)蛋白将细胞胆固醇转移到细胞外缺乏脂肪的载脂蛋白上。 ABCA1基因的过表达也被发现抑制淀粉样蛋白的形成。因此，我们设置了 致力于开发能够增加ABCA1和/或LDLR，同时降低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的沉积。 并对阿尔茨海默氏症提供治疗益处。 五个三芳基甲胺(TAMA)小分子成为降低载脂蛋白E的第一个先导 蛋白质水平(&gt；人脑星形细胞瘤细胞系减少30%，用酶联免疫吸附试验分析)。这个 TAMA药效团的作用机制是通过LXR拮抗作用。结构-活性 TAMA药效团在聚焦文库五个阶段的关系(SAR)研究，确定 五个类药物三芳基磺胺和芳香胺作为新的线索。它们不仅降低了载脂蛋白E水平 在体外，也增加了ABCA1/Ldlr蛋白水平，并通过浓度依赖研究证实。 纯R/S形式的三个手性先导对ApoE和ABCA1升高的作用不成比例 可能有多个目标。作为8个前导之一，化合物127调节了 转基因小鼠的大脑正在进行初步的体内研究。127的体内疗效验证了它的有效性 通过血脑屏障(BBB)的能力。初步的体外毒理学实验显示 这8种先导化合物是无毒的。 Sure支持将使Pi和他的本科生/研究生研究团队能够利用 在较新和更有效的磺胺类引线中发现关键附件的TAMA药效团 以产生新的和新颖的支架为基础的线索。这些支架预计会更轻，像毒品一样， 化学和药代动力学稳定，亲油性较差。PI的目标是进行化学合成 和生物筛查在他的实验室里，在一位忠诚的顾问的指导下。