Advances in Multi-Functional Ligands and the Need for Metal-Related Pharmacology for the Management of Alzheimer Disease.
Advances in Multi-Functional Ligands and the Need for Metal-Related Pharmacology for the Management of Alzheimer Disease.
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DOI：
10.3389/fphar.2018.01247
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发表时间：
2018
影响因子：
5.6
通讯作者：
Flora SJS
中科院分区：
文献类型：
--
作者：
Sharma A;Pachauri V;Flora SJS
阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病，目前还没有可用的疾病修正疗法。现有的治疗方法只能提供短期的症状缓解。对于这种疾病的发病机制，人们提出了几种假说，而这些分子在过去十年里被开发为可能的治疗剂，但在临床试验中基本上失败了。Tau蛋白过度磷酸化、A-β(A-β)多肽聚集、乙酰胆碱酯酶下降和氧化应激等因素可能参与了AD的发病过程。此外，据报道，脑中的生物金属代谢紊乱(铁、铜和锌)也参与了AD的发病机制。因此，靶向这些金属离子可能是开发治疗阿尔茨海默病药物的有效策略。目前对金属中毒采用的是螯合疗法，但我们缺乏一种安全有效的具有额外生物学特性的螯合剂，使其可以作为多靶点定向配体用于治疗像AD这样的复杂疾病。螯合剂具有解聚Aβ聚集体、溶解淀粉样斑块、延缓认知功能障碍的能力。因此，迫切需要开发具有多种有益功能的疾病修饰治疗分子，如靶向不止一个导致疾病的因素。这些分子作为AD的疾病修饰治疗剂，应该具有抑制Aβ-金属相互作用、形成有毒的Aβ聚集体以及恢复金属动态平衡的能力。
Alzheimer’s disease (AD) is the age linked neurodegenerative disorder with no disease modifying therapy currently available. The available therapy only offers short term symptomatic relief. Several hypotheses have been suggested for the pathogenesis of the disease while the molecules developed as possible therapeutic agent in the last decade, largely failed in the clinical trials. Several factors like tau protein hyperphosphorylation, amyloid-β (Aβ) peptide aggregation, decline in acetyl cholinesterase and oxidative stress might be contributing toward the pathogenesis of AD. Additionally, biometals dyshomeostasis (Iron, Copper, and Zinc) in the brain are also reported to be involved in the pathogenesis of AD. Thus, targeting these metal ions may be an effective strategy for the development of a drug to treat AD. Chelation therapy is currently employed for the metal intoxication but we lack a safe and effective chelating agents with additional biological properties for their possible use as multi target directed ligands for a complex disease like AD. Chelating agents possess the ability to disaggregate Aβ aggregation, dissolve amyloid plaques, and delay the cognitive impairment. Thus there is an urgent need to develop disease modifying therapeutic molecules with multiple beneficial features like targeting more than one factor responsible of the disease. These molecules, as disease modifying therapeutic agents for AD, should possess the potential to inhibit Aβ-metal interactions, the formation of toxic Aβ aggregates; and the capacity to reinstate metal homeostasis.
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