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 journalArticle

Abstract

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
Volume136
Issue number17
DOIs
StatePublished - Apr 30 2014

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Myotonic Dystrophy
Poisons
RNA
ligand
targeting
inhibitor
Ligands
Toxicity
Myotonia
toxicity
Alternative Splicing
Cell Nucleus
Cell culture
Drosophila
Cell Culture Techniques
Lead
Cells
bisamidinium

ASJC Scopus subject areas

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

Cite this

Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor. / Wong, Chun Ho; Nguyen, Lien; Peh, Jessie; Luu, Long M.; Sanchez, Jeannette S.; Richardson, Stacie L.; Tuccinardi, Tiziano; Tsoi, Ho; Chan, Wood Yee; Chan, H. Y.Edwin; Baranger, Anne M.; Hergenrother, Paul J.; Zimmerman, Steven C.

In: Journal of the American Chemical Society, Vol. 136, No. 17, 30.04.2014, p. 6355-6361.

Research output: Contribution to journalArticle

Wong, CH, Nguyen, L, Peh, J, Luu, LM, Sanchez, JS, Richardson, SL, Tuccinardi, T, Tsoi, H, Chan, WY, Chan, HYE, Baranger, AM, Hergenrother, PJ & Zimmerman, SC 2014, 'Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor', Journal of the American Chemical Society, vol. 136, no. 17, pp. 6355-6361. https://doi.org/10.1021/ja5012146
Wong, Chun Ho ; Nguyen, Lien ; Peh, Jessie ; Luu, Long M. ; Sanchez, Jeannette S. ; Richardson, Stacie L. ; Tuccinardi, Tiziano ; Tsoi, Ho ; Chan, Wood Yee ; Chan, H. Y.Edwin ; Baranger, Anne M. ; Hergenrother, Paul J. ; Zimmerman, Steven C. / Targeting toxic RNAs that cause myotonic dystrophy type 1 (DM1) with a bisamidinium inhibitor. In: Journal of the American Chemical Society. 2014 ; Vol. 136, No. 17. pp. 6355-6361.
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