摘要
自Tau蛋白聚集抑制剂吩噻嗪发现后,许多其它的多化学型小分子抑制剂被发现,并且在生物模式系统中表征。虽然直接tau聚集抑制剂显示具有阻止阿尔茨海默病神经纤维受损形成的治疗潜质,但是这些化合物的作用机制尚未清楚。然而,近期研究发现tau聚集拮抗剂通过共价和非共价方式发挥他们的作用,并且鉴定了相关的潜力和选择性驱动特征。在此我们对小分子tau聚集抑制剂的化学结构式和抑制机制进行了综述。阐明抑制机制,使靶点效应最大化,脱靶副作用最小化。
关键词: 阿尔茨海默病,聚集,神经元纤维缠结,成对螺旋细丝,tau蛋白
Current Alzheimer Research
Title:Structure and Mechanism of Action of Tau Aggregation Inhibitors
Volume: 11 Issue: 10
Author(s): Katryna Cisek, Grace L. Cooper, Carol J. Huseby and Jeff Kuret
Affiliation:
关键词: 阿尔茨海默病,聚集,神经元纤维缠结,成对螺旋细丝,tau蛋白
摘要: Since the discovery of phenothiazines as tau protein aggregation inhibitors, many additional small molecule inhibitors of diverse chemotype have been discovered and characterized in biological model systems. Although direct inhibition of tau aggregation has shown promise as a potential treatment strategy for depressing neurofibrillary lesion formation in Alzheimer’s disease, the mechanism of action of these compounds has been unclear. However, recent studies have found that tau aggregation antagonists exert their effects through both covalent and non-covalent means, and have identified associated potency and selectivity driving features. Here we review small-molecule tau aggregation inhibitors with a focus on compound structure and inhibitory mechanism. The elucidation of inhibitory mechanism has implications for maximizing on-target efficacy while minimizing off-target side effects.
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Katryna Cisek, Grace L. Cooper, Carol J. Huseby and Kuret Jeff, Structure and Mechanism of Action of Tau Aggregation Inhibitors, Current Alzheimer Research 2014; 11 (10) . https://dx.doi.org/10.2174/1567205011666141107150331
DOI https://dx.doi.org/10.2174/1567205011666141107150331 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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