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.

阿尔茨海默氏病是影响5000万的最常见无法治愈的痴呆形式 全球个人。载脂蛋白E4（APOE4）是直接的强遗传危险因素 与其发病机理有关。 APOE是一种隐含在 阿尔茨海默氏病，衰老和其他神经系统疾病。同工型依赖性淀粉样蛋白 在人类和小鼠中发现了APOE4的积累和清除。 APOE4和可能的APOE3的单倍不足降低了淀粉样病理学。低密度 脂蛋白受体（LDLR）在APOE蛋白的内吞作用中起重要作用。 ldlr 已经发现过表达可降低APOE水平并抑制淀粉样蛋白的形成。此外， Apoe在脂质中的作用会影响阿尔茨海默氏症的发病机理。 ATP结合盒转运蛋白A1 （ABCA1）蛋白质将细胞胆固醇转移到细胞外脂肪贫民窟的载脂蛋白上。 还发现ABCA1基因的过表达抑制淀粉样蛋白的形成。因此，我们设定了 开发出可以增加ABCA1和/或LDLR的小有机分子，同时降低APOE 蛋白质水平。这种化合物可能会减少并清除受影响的 大脑并为阿尔茨海默氏病提供治疗益处。 随着第一位铅的降低，五个三甲基胺（TAMA）小分子出现了 蛋白质水平（使用ELISA分析的人星形细胞瘤脑细胞系降低> 30％）。 TAMA PharmaCochore的作用机理是通过LXR拮抗作用。结构活性 关于tama PharmaCotore的关系（SAR）研究，分别是五个阶段的聚焦文库 五个药物样的三叶磺酰胺和芳基胺作为新铅。他们不仅开发了apoe级别 体外，但还增加了通过浓度依赖性研究验证的ABCA1/LDLR蛋白水平。 纯r/s形式中的三个手性导线对apoe和abca1的影响不成比例 多个目标的可能性。 8条铅之一，化合物127调节了目标蛋白 转基因小鼠大脑在体内研究中。成功的体内效率为127验证了其 能够通过血脑屏障（BBB）的能力。初步的体外毒理学实验揭示了所有 8种铅化合物无毒。 确定的支持将使PI及其本科/研究生研究团队能够利用 TAMA药效团具有关键的附属物 产生新的和新颖的基于脚手架的潜在客户。这些脚手架有望更轻，类似药物， 化学和药代动力学稳定，较少的亲脂性。 PI旨在执行化学合成 在实验室的指导下，在他的实验室中筛查生物学筛查。