基于药效团的阿尔茨海默病磷酸化tau 治疗药物模型。
Pharmacophore-based models for therapeutic drugs against phosphorylated tau in Alzheimer's disease.
机构信息
Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA.
Pharmacology & Neuroscience Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA.
出版信息
Drug Discov Today. 2019 Feb;24(2):616-623. doi: 10.1016/j.drudis.2018.11.005. Epub 2018 Nov 16.
Abstract
Phosphorylated tau (P-tau) has received much attention in the field of Alzheimer's disease (AD), as a potential therapeutic target owing to its involvement with synaptic damage and neuronal dysfunction. The continuous failure of amyloid β (Aβ)-targeted therapeutics highlights the urgency to consider alternative therapeutic strategies for AD. The present review describes the latest developments in tau biology and function. It also explains abnormal interactions between P-tau with Aβ and the mitochondrial fission protein Drp1, leading to excessive mitochondrial fragmentation and synaptic damage in AD neurons. This article also addresses 3D pharmacophore-based drug models designed to treat patients with AD and other tauopathies.
摘要
磷酸化 tau（P-tau）在阿尔茨海默病（AD）领域受到广泛关注，作为一种潜在的治疗靶点，因为它与突触损伤和神经元功能障碍有关。淀粉样蛋白β（Aβ）靶向治疗的持续失败突显了考虑 AD 替代治疗策略的紧迫性。本综述描述了 tau 生物学和功能的最新进展。它还解释了 P-tau 与 Aβ和线粒体分裂蛋白 Drp1 之间异常相互作用，导致 AD 神经元中过度的线粒体碎片化和突触损伤。本文还讨论了基于 3D 药效团的药物模型，旨在治疗 AD 和其他 tau 病患者。
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2
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3
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6
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7
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8
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9
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