Chemo-enzymatic synthesis of multivalent dendritic architectures for the control of neurodegenerative disorders

阿尔茨海默病（AD）是一种进行性神经退行性疾病，影响着全世界3000多万人。神经炎症以神经胶质过度激活和促炎细胞因子和趋化因子的过量产生为特征，在AD及相关神经退行性疾病的神经变性发病机制中起关键作用。阿尔茨海默病的特征之一是淀粉样肽的聚集，它在大脑中形成淀粉样斑块。金属离子如Cu（II）被认为在淀粉样蛋白的形成和这种进行性神经退行性疾病的发病中起作用。铜稳态调节是设计治疗阿尔茨海默病候选药物的潜在策略之一。早期的动物研究报道，正常或升高的Cu（II）水平可以抑制甚至去除AD相关的病理斑块。另一种验证AD大脑中铜稳态调节的可能性是使用合适的螯合剂，这些螯合剂能够通过竞争性结合和释放将铜离子从淀粉样蛋白- β肽转移到常规蛋白。这种配体作为载体配体的单价结合策略的能力已经在体外文献中进行了尝试。然而，许多传统金属螯合剂的血脑屏障（BBB）和神经毒性限制了它们在阿尔茨海默病或其他神经退行性疾病中的应用。综合药物化学数据库中只有5%的药物以中枢神经系统为靶点。因此，铜离子/螯合剂在血脑屏障上的运输是我们治疗方法的关键问题。纳米粒子传递系统已知可以穿过血脑屏障，这促使我们研究螯合剂与纳米粒子的结合是否可以逆转金属离子诱导的蛋白质沉淀。树突状纳米颗粒（NP）最近被报道在一个合作者的实验室（Haag， FUB）中运输Cu（II）离子穿过血脑屏障（BBB）。尽管在体外血脑屏障模型中铜的转运显著增加，但树枝状铜复合物在体内太不稳定。在此，建议将研究扩展到多个维度。我们建议在纳米尺寸的转运体中设计更稳定但可切割的铜配合物，这可能是有益的，因为它们可以被定制以优化其性能，如水动力尺寸，表面电荷和导电运输，以达到预期的应用领域。

Alzheimers disease (AD) is a progressive neurodegenerative disease that affects more than 30 million people worldwide. Neuro inflammation, characterized by excessive glial activation and overproduction of proinflammatory cytokine and chemokines, plays a critical role in the pathogenesis of neurodegeneration in AD and related neurodegenerative disorders. One of the hallmarks of AD is the aggregation of the amyloid beta peptide, which forms amyloid plaques in the brain. Metal ions such as Cu(II) have been proposed to play a role in amyloid formation and the onset of this progressive neurodegenerative disorder. Regulation of copper homeostasis is one of the potential strategies for the design of drug candidates for the treatment of AD. Earlier studies in animals have reported that normalized or elevated Cu(II) levels can inhibit or even remove AD related pathological plaques. Another possibility to validate the regulation of copper homeostasis in an AD brain is to use appropriate chelators capable of copper ion transfer from amyloid-beta peptide to regular proteins via competitive binding and release. The ability of such ligands to behave as vehicle ligands for a monovalent binding strategy has been attempted in vitro in the literature. However, the blood brain barrier (BBB) and neurotoxicity of many traditional metal chelators has limited their utility in AD or other neurodegenerative disorders. Only 5% of the drugs listed in the Comprehensive Medicinal Chemistry database target the CNS. Therefore, the transport of Cu ions / chelators over the BBB is a critical issue for our therapeutic approach. Nanoparticle delivery systems are known to cross the blood brain barrier and this has led us to investigate whether chelators delivered conjugated to nanoparticles could act to reverse metal ion induced protein precipitation. Dendritic nanoparticles (NP) have recently been reported for the transport of Cu(II) ions across the blood brain barrier (BBB) in the laboratory of one of the collaborators (Haag, FUB). Although the copper transport was dramatically increased in an in vitro BBB model, yet the dendritic copper complex was too instable in vivo. Herein it is proposed to extend the study in multiple dimensions. We propose the design of more stable but cleavable copper complexes within nanometer sized transporters that may be beneficial because they can be tailored to optimize their properties, such as hydrodynamic size, surface charges, and conductive transport, to the area of the intended application.