Wong, C.H., Nguyen, L., Peh, J., Luu, L.M., Sanchez, J.S., Richardson, S.L., Tuccinardi, T., Tsoi, H., Chan, W.Y., Chan, H.Y., Baranger, A.M., Hergenrother, P.J., Zimmerman, S.C. (2014). Targeting Toxic RNAs that Cause Myotonic Dystrophy Type 1 (DM1) with a Bisamidinium Inhibitor.  J. Am. Chem. Soc. 136(17): 6355--6361.

FBrf0224846

Research paper

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.

PMC4015652 (PMC) (EuropePMC)