Many diseases are caused by toxic RNA repeats. Herein, we designed a lead small molecule that binds the structure of the r(CUG) repeat expansion [r(CUG)^exp] that causes myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD) and rescues disease biology in patient-derived cells and in vivo. Interestingly, the compound's downstream effects are different in the two diseases, owing to the location of the repeat expansion. In DM1, r(CUG)^exp is harbored in the 3′ untranslated region, and the compound has no effect on the mRNA's abundance. In FECD, however, r(CUG)^exp is located in an intron, and the small molecule facilitates excision of the intron, which is then degraded by the RNA exosome complex. Thus, structure-specific, RNA-targeting small molecules can act disease specifically to affect biology, either by disabling the gain-of-function mechanism (DM1) or by stimulating quality control pathways to rid a disease-affected cell of a toxic RNA (FECD).

许多疾病是由有毒的 RNA 重复序列引起的。在这里，我们设计了一种先导小分子，它与 r(CUG) 重复扩展 [r(CUG) ^exp ] 的结构结合，导致 1 型强直性营养不良 (DM1) 和 Fuchs 角膜内皮营养不良 (FECD) 并挽救患者的疾病生物学衍生细胞和体内。有趣的是，由于重复扩增的位置，该化合物的下游效应在这两种疾病中是不同的。在 DM1 中，r(CUG) ^exp位于 3' 非翻译区，该化合物对 mRNA 的丰度没有影响。然而，在 FECD 中，r(CUG) ^exp位于内含子中，小分子促进内含子的切除，然后被RNA外泌体复合物降解。因此，结构特异性、靶向 RNA 的小分子可以通过禁用功能获得机制 (DM1) 或通过刺激质量控制途径来消除受疾病影响的细胞中的毒性 RNA，从而特异性地作用于疾病以影响生物学。 FECD)。