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

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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.