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

基本信息

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
项目类别：
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&apos 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

项目摘要

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 万人载脂蛋白 E4 (APOE4) 是直接影响全球个体的最强遗传风险因素。 ApoE 是一种胆固醇和脂质载体蛋白，与它的发病机制有关。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影响。在 APOE4 受到困扰的人类和小鼠中发现了积累和清除。 ApoE4 和可能的 ApoE3 的单倍体不足会降低低密度淀粉样蛋白病理。脂蛋白受体 (LDLR) 在 ApoE 蛋白的内吞作用中发挥重要作用。已发现过度表达可降低 ApoE 水平并抑制淀粉样蛋白形成。 ApoE 在脂化中的作用影响阿尔茨海默病的发病机制。 (AbcA1) 蛋白将细胞胆固醇转移到细胞外的贫脂载脂蛋白上。 ABCA1基因的过度表达也被发现可以抑制淀粉样蛋白的形成，因此，我们设定。致力于开发可增加 AbcA1 和/或 Ldlr 同时减少 ApoE 的有机小分子此类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（使用 ELISA 分析，人星形细胞瘤脑细胞系减少 >30%）。 TAMA 药效团的作用机制是通过 LXR 拮抗作用。重点文库五个阶段中 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 8 个先导化合物之一，化合物 127 调节靶蛋白。转基因小鼠大脑的初步体内研究127的成功验证了其体内功效。初步体外毒理学实验揭示了通过血脑屏障（BBB）的能力。 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、新颖的基于支架的先导化合物，这些支架预计会更轻，类似药物，化学和药代动力学稳定，亲脂性较低，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。