Myotonic dystrophy (DM) is a genetic neuromuscular disease for which there is no current treatment available, only palliative therapy. The most common form of this disease, myotonic dystrophy type 1 (DM1), is caused by a progressive expansion of a CTG repeat in the 3'-untranslated region of the DMPK gene. The resulting expanded CUG repeat (CUGexp) transcripts sequester MBNL1, a key regulatory protein of alternative splicing, to create ribonuclear foci composed of MBNL1�CUGexp aggregates. The disruption of these foci and restoration of MBNL1 function is of increasing interest because it reverses the disease phenotype in mouse models. Thus, presented here is the design, synthesis and evaluation of a small library of bivalent ligands for inhibition of CUGexp�MBNL1 interaction based on a small molecule previously found to be active in an in vitro assay.

Developing bivalent ligands to target CUG triplet repeats, the causative agent of myotonic dystrophy type 1

247th National Meeting (2014)

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