Myotonic dystrophy (DM) is currently an incurable genetic disease which affecting 1 in 8,000 human worldwide. One promising approach to treat myotonic dystrophy is the development of nucleic acid binders that can selectively inhibit the complex formation between the MBNL1 protein and expanded RNA repeats. Our group has synthesized ligands that recognize the key feature in the RNA repeats � the U-U mismatch in CUG and C-U in CCUG. We found that ligand 1 binds selectively to U-U mismatches (and T-T in DNA) and inhibits the MBNL1-RNA complexation in vitro. Nevertheless, the binding modes for both U-U and T-T mismatches were not fully characterized. We utilized a combination of synthesis, biophysical techniques, and molecular dynamics simulations to elucidate the binding modes of these ligands. Two different binding modes were observed for U-U mismatches in dsRNA and T-T mismatches in dsDNA. The results should allow new ligand design for better inhibitory activity.

Modes of nucleic acid binding of small molecule inhibitors for MBNL1[times]RNA complexation in myotonic dystrophy Type 1 (DM1)

242nd National Meeting (2011)

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