Small molecules exploiting structural differences within microRNA-200 precursors family members reverse a type 2 diabetes phenotype

MicroRNA families are pervasive in the human transcriptome, but specific targeting of individual members is a challenge because of sequence homology. Many of the secondary structures of the precursors to these miRs (pre-miRs), however, are quite different. Here, we demonstrate both in vitro and in cellulis that design of structure-specific small molecules can inhibit specific miR family members to modulate a disease pathway. In particular, the miR-200 family consists five miRs, miR-200a, -200b, -200c, -141, and -429, and is associated with Type II Diabetes (T2D). We designed a small molecule that potently and selectively targets pre-miR-200c[primer]s structure. The compound reverses a pro-apoptotic effect in a pancreatic beta-cell model. In contrast, oligonucleotides targeting the RNA[prime]s sequence inhibit all family members. Global proteomics analysis further demonstrates selectivity for miR-200c. Collectively, these studies establish that miR-200c plays an important role in T2D and that small molecules targeting RNA structure can be an important complement to oligonucleotides targeting sequence.