Departments of Chemistry and Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA.
Mitchell Center for Neurodegenerative Disorders, Department of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Nat Commun. 2016 Jun 1;7:11647. doi: 10.1038/ncomms11647.
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.
RNA 是功能化学探针和潜在治疗药物的重要靶标；然而，用小分子靶向它是困难的。解决这个问题的一种方法是识别靶向 RNA 结构的化合物，并利用它们多价靶向 RNA。在这里，我们表明可以通过探测 RNA 小分子文库来鉴定出选择性结合 RNA 碱基对的小分子。选择性结合 AU 碱基对的小分子为设计靶向致病 RNA，即扩张的 r(AUUCU) 重复序列的二聚体化合物（2AU-2）提供了信息，该化合物导致 10 型脊髓小脑共济失调（SCA10）在患者来源的细胞中。事实上，2AU-2（50 nM）改善了 SCA10 病理的各个方面，包括改善线粒体功能障碍、降低半胱天冬酶 3 的激活和减少核焦点。这些研究提供了一种用于研究 SCA10 RNA 毒性的首创化学探针，并可能定义了在细胞中靶向 RNA AU 碱基对的广泛适用的化合物。
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