A Small Molecule That Targets r(CGG)exp and Improves Defects in Fragile X-Associated Tremor Ataxia Syndrome
A Small Molecule That Targets r(CGG)exp and Improves Defects in Fragile X-Associated Tremor Ataxia Syndrome
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DOI：
10.1021/cb300135h
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发表时间：
2012-10-01
影响因子：
4
通讯作者：
Childs-Disney, Jessica L.
中科院分区：
文献类型：
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作者：
Disney, Matthew D.;Liu, Biao;Childs-Disney, Jessica L.
尽管人们对此类化合物非常感兴趣，但针对 RNA 的小分子化学探针或疗法的开发仍然是一个重大挑战。化合物开发的最重要障碍是定义哪些化学和 RNA 基序空间特异性相互作用。在此，我们描述了一种生物活性小分子探针，其靶向扩展的 r(CGG) 重复序列或 r(CGG)(exp)，导致脆性 X 相关震颤共济失调综合征 (FXTAS)。该化合物是通过使用化学型和相互作用的 RNA 基序的信息来鉴定的。具体而言，9-羟基-5,11-二甲基-2-(2-(哌啶-1-基)乙基)-6H-pyrido[4,3-b]carbazol-2-ium 结合 r(CGG)(exp) 中的 5'CGG/3'GGC 基序，并在体外破坏有毒的 r(CGG)(exp)-蛋白复合物。构效关系研究确定烷基化吡啶基和酚侧链是驱动 r(CGG)(exp) 分子识别的重要化学型。重要的是，该化合物在 FXTAS 模型细胞系统中有效，其能够改善 FXTAS 相关的前 mRNA 剪接缺陷并减少含有 r(CGG)(exp) 的核灶的大小和数量，证明了这一点。这种方法可以建立一个通用策略来识别靶向 RNA 的先导配体，同时还提供化学探针来剖析 r(CGG)(exp) 促进毒性的各种机制。
The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is defining which chemical and RNA motif spaces interact specifically. Herein, we describe a bioactive small molecule probe that targets expanded r(CGG) repeats, or r(CGG)(exp), that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium binds the 5'CGG/3'GGC motifs in r(CGG)(exp) and disrupts a toxic r(CGG)(exp)-protein complex in vitro. Structure-activity relationship studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG)(exp). Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)(exp)-containing nuclear foci. This approach may establish a general strategy to identify lead ligands that target RNA while also providing a chemical probe to dissect the varied mechanisms by which r(CGG)(exp) promotes toxicity.