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 bothin vitroandin cellulisthat 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’s structure. The compound reverses a pro-apoptotic effect in a pancreatic β-cell model. In contrast, oligonucleotides targeting the RNA’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.