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

阿尔茨海默病（AD）是最主要的与痴呆相关的神经退行性疾病。引发神经元丧失的主要机制方面仍然隐藏在黑暗中，适当的检测和诊断这种疾病是一个主要障碍。除了神经原纤维缠结（NFT）在脑内聚集外，AD的主要特征是（不溶性）β-淀粉样蛋白（a β）在脑内大量积聚，导致神经毒性斑块。只有一大堆的阿尔茨海默病药物被批准并用于治疗，只治疗阿尔茨海默病的症状，而不是主要原因。ABC转运蛋白的功能在大脑清除a β蛋白以防止斑块聚集方面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重建可减轻AD影响小鼠的Aβ蛋白负荷并改善其认知功能。三个代表- ABCB1 (P-gp), ABCC1 （MRP1）和ABCG2 (BCRP) -与Aβ蛋白通过血脑屏障从大脑进入血流的（直接）清除有关。这些ABC转运蛋白既没有真正的选择性或广谱激活剂，也没有尝试开发。考虑到文献中关于ABC转运蛋白激动剂的报道很少，本项目的目的是设计和合成所述ABC转运蛋白的新激活剂，并在基于活细胞的荧光积累试验中对其进行评估。现有的和新导出的数据将被考虑开发一个计算模型，用于大规模虚拟化合物库的计算机筛选，以预测假定的选择性和多靶点ABCB1， ABCC1和ABCG2激动剂。本项目合作者的互补、大型模拟化合物库将通过已建立的转运蛋白分析进行筛选，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）测试系统。最后，将评估这些命中分子诱导ABC转运蛋白的能力。

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.