Design, synthesis, and biological assessment of ABC transporter agonists for the development of novel Alzheimer’s disease therapeutics

用于开发新型阿尔茨海默病疗法的 ABC 转运蛋白激动剂的设计、合成和生物学评估

• 批准号: 446812474
• 负责人: Dr. Sven Marcel Stefan
• 金额: --
• 依托单位: Lübecker Institut für Experimentelle Dermatologie (LIED)
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/446812474?language=en
• 关键词: Design; synthesis; biological; assessment; ABC

Alzheimer’s disease (AD) is the most dominant, dementia-related neurodegenerative disease. The main mechanistic aspects initiating the loss of neurons is still hidden in the dark, and proper detection as well as diagnosis of this illness is a major obstacle. Besides the intracerebral aggregation of neurofibrillary tangles (NFT), AD is mainly characterized by a massive accumulation of (insoluble) β-Amyloid (Aβ) proteins in the brain leading to neurotoxic plaques. Only a hand full of AD pharmaceuticals are approved and in therapeutic use, treating only symptoms of AD, but not the prevalent cause(s). ABC transport protein function plays a crucial role in clearance of Aβ proteins from the brain to prevent plaque aggregation. In AD pathogenesis, downregulation of ABC transporters in affected vessels has been proven, and their reconstitution by induction of these transporters lessened Aβ protein burden and improved cognitive features of AD-affected brains in mice. Three representatives – ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) – stand in association with (direct) clearance of Aβ proteins from the brain to the blood stream over the blood brain barrier. Neither a genuine selective or broad-spectrum activator of these ABC transport proteins is available, nor has it been tried to develop.Taking the scarce reports on ABC transporter agonists in literature into account, the aim of this project is to design and synthesize new activators of the stated ABC transporters and evaluate these in living cell-based fluorescence accumulation assays. Existing and newly derived data will be considered to develop a computational model for in silico screenings of huge virtual compound libraries to predict putative selective as well as multi-target ABCB1, ABCC1, and ABCG2 agonists. Complementary, large analog compound libraries of collaborators of this project will be screened with established transporter assays to discover new leads for further synthetic structure optimization. Promising hit molecules will be used to establish an Aβ protein-based high-throughput-screening (HTS) testing system. Finally, these hit molecules will be assessed for their capability to induce ABC transporters.

阿尔茨海默病（Alzheimer's disease，AD）是最常见的与痴呆相关的神经退行性疾病。引发神经元损失的主要机制方面仍然隐藏在黑暗中，对这种疾病的适当检测和诊断是一个主要障碍。除了神经元缠结（NFT）的脑内聚集外，AD的主要特征是（不溶性）β-淀粉样蛋白（Aβ）在脑中的大量积聚，导致神经毒性斑块。只有大量的AD药物被批准并用于治疗，仅治疗AD的症状，而不是普遍的原因。ABC转运蛋白功能在从脑中清除Aβ蛋白以防止斑块聚集中起着至关重要的作用。在AD发病机制中，已证实受影响血管中ABC转运蛋白的下调，通过诱导这些转运蛋白的重建减轻了Aβ蛋白负荷，改善了AD影响小鼠大脑的认知功能。三种代表性药物-ABCB 1（P-gp）、ABCC 1（MRP 1）和ABCG 2（BCRP）-与Aβ蛋白通过血脑屏障从脑到血流的（直接）清除相关。既不是一个真正的选择性或广谱激活剂，这些ABC转运蛋白是可用的，也没有试图开发，考虑到文献中的ABC转运蛋白激动剂的稀缺报告，本项目的目的是设计和合成新的激活剂所述ABC转运蛋白和评估这些活细胞为基础的荧光积累试验。现有的和新获得的数据将被认为是开发一个计算模型，用于在计算机上筛选巨大的虚拟化合物库，以预测推定的选择性以及多靶点ABCB 1，ABCC 1和ABCG 2激动剂。该项目的合作者的互补的大型类似物化合物库将使用已建立的转运蛋白测定进行筛选，以发现进一步合成结构优化的新线索。有希望的命中分子将用于建立基于Aβ蛋白的高通量筛选（HTS）检测系统。最后，将评估这些命中分子诱导ABC转运蛋白的能力。