MicroRNA families are ubiquitous in the human transcriptome, yet targeting of individual members is challenging because of sequence homology. Many secondary structures of the precursors to these miRNAs (pri- and pre-miRNAs), however, are quite different. Here, we demonstrate both in vitro and in cellulis that design of structure-specific small molecules can inhibit a particular miRNA family member to modulate a disease pathway. The miR-200 family consists of five miRNAs, miR-200a, -200b, -200c, -141, and -429, and is associated with type 2 diabetes (T2D). We designed a small molecule that potently and selectively targets pre-miR-200c’s structure and reverses a pro-apoptotic effect in a pancreatic β cell model. In contrast, an oligonucleotide targeting the RNA’s sequence inhibited all family members. Global proteomics and RNA sequencing analyses further demonstrate selectivity for miR-200c. Collectively, these studies establish that miR-200c plays an important role in T2D, and small molecules targeting RNA structure can be an important complement to oligonucleotides.

MicroRNA 家族在人类转录组中无处不在，但由于序列同源性，靶向单个成员具有挑战性。然而，这些 miRNA 前体（pri- 和 pre-miRNA）的许多二级结构非常不同。在这里，我们展示了体外和蜂窝组织结构特异性小分子的设计可以抑制特定的 miRNA 家族成员来调节疾病途径。miR-200 家族由五个 miRNA 组成，miR-200a、-200b、-200c、-141 和 -429，与 2 型糖尿病 (T2D) 相关。我们设计了一种小分子，可有效且选择性地靶向 pre-miR-200c 的结构并逆转胰腺 β 细胞模型中的促凋亡作用。相比之下，靶向 RNA 序列的寡核苷酸抑制所有家族成员。全局蛋白质组学和 RNA 测序分析进一步证明了 miR-200c 的选择性。总的来说，这些研究表明 miR-200c 在 T2D 中起着重要作用，靶向 RNA 结构的小分子可以成为寡核苷酸的重要补充。