Drugging unconventional targets: insights from Huntington's disease
Drugging unconventional targets: insights from Huntington's disease
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对非常规靶点进行药物治疗：亨廷顿舞蹈病的见解
DOI：
10.1016/j.tips.2013.12.001
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发表时间：
2014
影响因子：
13.8
通讯作者：
Lu Boxun
中科院分区：
文献类型：
--
作者：
Yu Shenliang;Liang Yijian;Palacino James;Difiglia Marian;Lu Boxun
经典的靶向药物发现是基于靶向可药用靶标，通常是其功能可以被激动或拮抗的激酶和受体。这种策略在诸如亨廷顿氏病（HD）和类似的神经退行性疾病的情况下遇到困难，其中引起疾病的蛋白质的病理功能不清楚。HD是由含有扩展的聚谷氨酰胺（polyQ）延伸的突变HTT蛋白（mHTT）引起的，但mHTT的功能以及mHTT如何引起HD尚不清楚，因此阻碍了筛选mHTT“替代物”的努力。然而，与其他主要的神经退行性疾病相比，HD对药物发现有吸引力，因为基因突变是明确的。虽然mHTT不是一个传统的“药物”目标，但一种似乎有希望的方法是降低其水平，这可能适用于与蛋白质异常积累相关的其他神经退行性疾病和蛋白质病。在这里，我们审查mHTT降低策略，可能提供有前途的途径药物治疗这些疾病。
Classical targeted drug discovery is based on targeting druggable targets, typically kinases and receptors of which the function can be agonized or antagonized. This strategy meets difficulties in cases such as Huntington's disease (HD) and similar neurodegenerative disorders, where the pathological function of the protein causing the disease is not clear. HD is caused by mutant HTT protein (mHTT) containing an expanded polyglutamine (polyQ) stretch, but the function of mHTT and how mHTT causes HD are unknown, thus preventing efforts to screen for mHTT ‘inhibitors'. However, HD is appealing for drug discovery because the genetic mutation is clear, as compared with other major neurodegenerative disorders. Although mHTT is not a conventional ‘druggable' target, one approach that appears promising is lowering its level, which might be applicable to other neurodegenerative disorders and proteinopathies linked to aberrant accumulation of proteins. Here we review mHTT lowering strategies that might provide promising avenues for drugging such diseases.