Precise small-molecule recognition of a toxic CUG RNA repeat expansion

Nat Chem Biol. 2017 Feb;13(2):188-193. doi: 10.1038/nchembio.2251. Epub 2016 Dec 12.


Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)exp) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG)exp. In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG)exp and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)exp in its natural context.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • RNA / chemistry*
  • RNA / drug effects*
  • RNA / genetics
  • RNA Splicing / drug effects
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Trinucleotide Repeat Expansion / drug effects*


  • Small Molecule Libraries
  • RNA

Associated data

  • PubChem-Substance/318835077
  • PubChem-Substance/318835080
  • PubChem-Substance/318835081
  • PubChem-Substance/318835082
  • PubChem-Substance/318835083
  • PubChem-Substance/318835084
  • PubChem-Substance/318835085
  • PubChem-Substance/318835086
  • PubChem-Substance/318835087
  • PubChem-Substance/318835088
  • PubChem-Substance/318835089
  • PubChem-Substance/318835090
  • PubChem-Substance/318835078
  • PubChem-Substance/318835079