Myotonic dystrophy type 1 (DM1) is one of the most common multisystem disorders affecting 1 in 8000 worldwide. DM1 occurs when there is an expansion of CTG repeats located in chromosome 19q in DMPK gene. The CTG repeat lengths less than 50 are considered normal, whereas lengths of 2000 CTG repeats represents an advanced disease state, the length directly related to severity and onset of the disease. Transcribed CUG repeat (CUGexp) forms a stable hairpin and sequesters the MBNL protein family including MBNL1, a regulator for alternative splicing. Depletion of MBNL proteins in nucleus causes the defect in alternative splicing of a set of more than 100 pre-mRNAs, which causes the disease phenotypes such as myotonia, muscle weakness, cataracts, cardiovascular problems, bilateral facial weakness and respiratory problems. To date, DM1 is incurable.One of approaches to treat DM1 is to target CUG repeats and thereby liberate the MBNL proteins for its normal functions. Taking advantage of the reported CUG repeat X-ray crystal structures, our group rationally designed recognition unit based on Janus-Wedge type binding to target UU mismatches in CUG repeats. A set of intercalators and RNA groove binders were synthesized by combining the recognition unit and known RNA binders such as acridine and bis-amidine motifs. Herein, we report the biological activities of the small molecules, which show that the optimized small molecules not only inhibit CUGexp�MBNL in vitro but also disrupt the disease foci and partially rescue alternative splicing defect of IR minigene.

Biological activity study of rationally designed small molecules for CUG<sup>exp</sup>�MBNL inhibition

246th National Meeting (2013)

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Biological activity study of rationally designed small molecules for CUGexp�MBNL inhibition

Biological activity study of rationally designed small molecules for CUG^exp�MBNL inhibition