Targeting Toxic RNAs that Cause Myotonic Dystrophy Type 1 (DM1) with a Bisamidinium Inhibitor
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AbstractA 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 DMI 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 mu M) and disrupts the MBNL1-r(CUG)(12) interaction in vitro (K-i = 8 +/- 2 mu M). 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 DMI Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1.
All Author(s) ListWong 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
Journal nameJournal of the American Chemical Society
Volume Number136
Issue Number17
Pages6355 - 6361
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesChemistry; Chemistry, Multidisciplinary; CHEMISTRY, MULTIDISCIPLINARY

Last updated on 2020-03-07 at 00:53