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

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 (K(d) = 8 ± 2 μM) and disrupts the MBNL1-r(CUG)12 interaction in vitro (K(i) = 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.

• Authors: 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
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 136 Issue 17 Pg. 6355-61 (Apr 30 2014) ISSN: 1520-5126 [Electronic] United States
• PMID: 24702247 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Imidazoles
• Mbnl1 protein, mouse
• RNA-Binding Proteins
• bisamidinium
• RNA

Topics

• Alternative Splicing (drug effects)
• Animals
• Base Sequence
• DNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Drosophila
• Drug Discovery
• HeLa Cells
• Humans
• Imidazoles (chemistry, pharmacology)
• Mice, Inbred C57BL
• Models, Molecular
• Molecular Targeted Therapy
• Myotonic Dystrophy (drug therapy, genetics, metabolism)
• Nucleic Acid Conformation (drug effects)
• RNA (antagonists & inhibitors, chemistry, genetics, metabolism)
• RNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Trinucleotide Repeat Expansion (drug effects)