Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10.
Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10.
复制标题
DOI：
10.1038/ncomms11647
复制
发表时间：
2016-06-01
影响因子：
16.6
通讯作者：
Disney MD
中科院分区：
文献类型：
--
作者：
Yang WY;Gao R;Southern M;Sarkar PS;Disney MD
RNA是功能和先导疗法的化学探针的重要靶标;然而，难以用小分子靶向。解决这个问题的一种方法是鉴定靶向RNA结构的化合物，并利用它们来多价靶向RNA。在这里，我们表明，小分子可以被确定为选择性地结合RNA碱基对通过探测的RNA聚焦的小分子库。选择性结合Au碱基对的小分子告知靶向致病性RNA（扩增的r（AUUCU）重复）的二聚化合物（2 Au-2）的设计，所述致病性RNA在患者来源的细胞中引起脊髓小脑共济失调10型（SCA 10）。事实上，2AU-2（50 nM）改善了SCA 10病理学的各个方面，包括改善线粒体功能障碍、减少半胱天冬酶3的活化和减少核灶。这些研究提供了一流的化学探针来研究SCA 10 RNA毒性，并可能定义靶向细胞中RNA Au碱基对的广泛适用的化合物。 在基因的非编码区中扩增的RNA重复序列代表了几种疾病的标志。在这里，作者鉴定了两种选择性结合Au重复序列的小分子，并使用它们设计了一种靶向与脊髓小脑共济失调10型相关的致病RNA的化合物。
RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells. Expanded RNA repeats in non-coding region of a gene represent a hallmark of several diseases. Here, the authors identify two small molecules that selectively bind AU repeats and use them to design a compound that targets the pathogenic RNA associated with spinocerebellar ataxia type 10.