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Design of a Bioactive Small Molecule that Targets the Myotonic Dystrophy Type 1 RNA Via an RNA Motif-Ligand Database Chemical Similarity Searching

机译：生物活性小分子设计为目标的强直性肌营养不良1型RNa通过RNa motif的配体数据库化学相似性搜索

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Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5′CUG/3′GUC motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Sequestration of MBNL1 by expanded r(CUG) repeats causes splicing defects in a subset of pre-mRNAs including the insulin receptor, the muscle-specific chloride ion channel, Sarco(endo)plasmic reticulum Ca2+ ATPase 1 (Serca1/Atp2a1), and cardiac troponin T (cTNT). Based on these observations, the development of small molecule ligands that target specifically expanded DM1 repeats could serve as therapeutics. In the present study, computational screening was employed to improve the efficacy of pentamidine and Hoechst 33258 ligands that have been shown previously to target the DM1 triplet repeat. A series of inhibitors of the RNA-protein complex with low micromolar IC50’s, which are >20-fold more potent than the query compounds, were identified. Importantly, a bis-benzimidazole identified from the Hoechst query improves DM1-associated pre-mRNA splicing defects in cell and mouse models of DM1 (when dosed with 1 mM and 100 mg/kg, respectively). Since Hoechst 33258 was identified as a DM1 binder through analysis of an RNA motif-ligand database, these studies suggest that lead ligands targeting RNA with improved biological activity can be identified by using a synergistic approach that combines analysis of known RNA-ligand interactions with virtual screening.
机译：肌肌营养不良型1（DM1）是由营养不良肌肌肌肌肌瘤蛋白激酶（DMPK）基因的3'未翻译区域中的膨胀CTG重复引起的三重态重复​​障碍。转录的重复折叠成具有5'Cug / 3'Guc基序的多个拷贝的RNA发夹，其结合RNA剪接调节剂肌肉样蛋白（MBNL1）。通过膨胀的R（Cug）脱模的MBNL1重复导致胰岛素受体的前MRNA子集中的剪切缺陷，包括肌肉受体，肌肉特异性氯离子通道，Sarco（endo）素质网状Ca 2 + AtP酶1（Serca1 / ATP2A1）和心肌肌钙蛋白T（CTNT）。基于这些观察结果，靶向特异性扩增DM1重复的小分子配体的发展可以用作治疗剂。在本研究中，使用计算筛选来改善先前已显示的偏心和Hoechst 33258配体的疗效以靶向DM1三重态重复​​。鉴定了一系列具有低微摩尔IC50的RNA蛋白络合物的抑制剂，其比查询化合物更高的高效率。重要的是，从Hoechst查询中鉴定的双苯并咪唑改善了DM1的细胞和小鼠模型中的DM1相关的前mRNA剪接缺陷（分别为1mm和100mg / kg时）。由于通过分析RNA MOTIF-LIGAND数据库，HOECHST 33258被鉴定为DM1粘合剂，因此可以通过使用与虚拟的已知RNA - 配体相互作用的协同方法相结合的协同方法来鉴定靶向具有改进的生物活性的RNA的铅配体。筛选。

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