LIED, Pahnke Lab (www.pahnkelab.eu), University of Lübeck and University Medical Center Schleswig-Holstein, Ratzeburger Allee 160, 23538 Lübeck, Germany; Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab (www.pahnkelab.eu), University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway.
Int J Biol Macromol. 2022 Sep 30;217:775-791. doi: 10.1016/j.ijbiomac.2022.07.062. Epub 2022 Jul 13.
Alzheimer's disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aβ and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aβ peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aβ could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aβ clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics.
阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，其特征是大分子 Aβ和 tau 的病理性积累，导致神经元死亡。已批准用于治疗 AD 的药物可以改善疾病症状，但目前尚无治愈方法。Aβ 肽是三磷酸腺苷（ATP）结合盒（ABC）转运体的底物。这些膜结合外排蛋白的激活剂可促进 Aβ 的结合和/或转运，可能会彻底改变 AD 的治疗方法。然而，关于 ABC 转运体激活剂的知识非常有限，据报道的少数分子含有多靶点（泛）ABC 转运体抑制剂的亚结构特征。探索和潜在利用最近提出的泛 ABC 转运体抑制剂的多靶点结合位点，作为开发创新型激活剂以促进 Aβ 从大脑清除的锚点，是获得新候选药物的前沿策略。小分子功能生物活性和理化性质之间的分子关联是理解这些过程的关键。本研究对最近报道的独特多靶点数据集进行了分析，以研究多靶点生物活性与理化性质之间的相关性。六种新型泛 ABC 转运体抑制剂得到了验证，其中包含 ABC 转运体激活剂的亚结构特征，这支持了多靶点结合位点对于针对 AD 诊断和治疗的新型药物的靶向开发的相关性。
