Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-β and amyloid-β protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways.

译文

阿尔茨海默氏病 (AD) 是一种多因素综合征,在其进展过程中涉及一系列复杂的不同而相关的因素。因此,可以同时调节多个与疾病相关的靶标的新颖方法为有效治疗AD带来了巨大希望。这篇综述描述了具有多峰活性的新型杂化分子的发展,包括: i) M30,具有螯合和神经保护活性的脑渗透性选择性单胺氧化酶 (MAO)-A和-B抑制剂; ii) HLA20,具有神经保护活性的脑渗透性金属螯合剂; iii) HLA20A,乙酰胆碱酯酶 (AChE) 抑制剂,具有位点激活的螯合和神经保护活性; iv) M30D,AChE和mao-a和-B抑制剂,具有位点激活的螯合和神经保护活性; v) 神经保护氨基酸肽的类似物NAPVSIPQ。HLA20A和M30D充当亲螯合剂,可以通过伪抑制AChE来激活其各自的活性螯合剂HLA20和M30。我们首先讨论这些新型化合物的合理设计的知识和基于结构的策略。然后,我们回顾了我们最近对这些候选药物的研究,关于它们在体外和体内的广泛活性,重点是抗氧化剂螯合效力和AchE和MAO-A和-B抑制活性,以及神经保护/神经受体作用。最后,我们讨论了这些化合物与AD相关的多种分子作用机制,包括淀粉样 β 和淀粉样 β 蛋白前体表达/加工的调节; 诱导细胞周期停滞; 抑制神经元死亡标志物; 和神经营养因子的上调,以及蛋白激酶信号通路的激活。

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