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Targeting TDP‐43 proteinopathy with drugs and drug‐like small molecules
British Journal of Pharmacology ( IF 7.3 ) Pub Date : 2020-05-29 , DOI: 10.1111/bph.15148
Emanuele Buratti 1
Affiliation  

Following the discovery of the involvement of the ribonucleoprotein TDP‐43 in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), a major research focus has been to develop treatments that can prevent or alleviate these disease conditions. One pharmacological approach has been to use TDP‐43‐based disease models to test small molecules and drugs already known to have some therapeutic effect in a variety of neurodegenerative conditions. In parallel, various disease models have been used to perform high‐throughput screens of drugs and small compound libraries. The aim of this review will be to provide a general overview of the compounds that have been described to alter pathological characteristics of TDP‐43. These include expression levels, cytoplasmic mis‐localization, post‐translational modifications, cleavage, stress granule recruitment and aggregation. In parallel, this review will also address the use of compounds that modify the autophagic/proteasome systems that are known to target TDP‐43 misfolding and aggregation.

中文翻译:

使用药物和类药物小分子靶向TDP-43蛋白病

在发现核糖核酸蛋白TDP-43参与了肌萎缩性侧索硬化症(ALS)和额颞叶变性(FTLD)之后,一项主要的研究重点是开发可以预防或减轻这些疾病状况的治疗方法。一种药理学方法是使用基于TDP-43的疾病模型来测试已知在各种神经退行性疾病中具有一定治疗作用的小分子和药物。同时,各种疾病模型已用于对药物和小型化合物库进行高通量筛选。这篇综述的目的是提供已描述的可改变TDP-43病理特征的化合物的一般概述。其中包括表达水平,胞质错定位,翻译后修饰,切割,应力颗粒募集和聚集。同时,本综述还将探讨使用修饰自噬/蛋白酶体系统的化合物,这些系统已知可靶向TDP-43错折叠和聚集。
更新日期:2020-05-29
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