Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor

Chun Ho Wong, Lien Nguyen, Jessie Peh, Long M. Luu, Jeannette S. Sanchez, Stacie L. Richardson, Tiziano Tuccinardi, Ho Tsoi, Wood Yee Chan, H. Y.Edwin Chan, Anne M. Baranger, Paul J. Hergenrother, Steven C. Zimmerman

Research output: Contribution to journalArticlepeer-review


A working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)exp. It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)exp interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. Ligand 3 binds r(CUG)12 with a low micromolar affinity (Kd = 8 ± 2 μM) and disrupts the MBNL1-r(CUG)12 interaction in vitro (Ki = 8 ± 2 μM). In addition, ligand 3 is cell and nucleus permeable, exhibits negligible toxicity to mammalian cells, dissolves MBNL1-r(CUG)exp ribonuclear foci, and restores misregulated splicing of IR and cTNT in a DM1 cell culture model. Importantly, suppression of r(CUG)exp RNA-induced toxicity in a DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1.

Original languageEnglish (US)
Pages (from-to)6355-6361
Number of pages7
JournalJournal of the American Chemical Society
Issue number17
StatePublished - Apr 30 2014

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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