Preclinical Development of Lead Compounds Targeting Myotonic Dystrophy

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DESCRIPTION (provided by applicant): Sequestration of MBNL1 by (CUG) repeat RNA is believed to be a key molecular interaction in type 1 myotonic dystrophy (DM1). Thus, new compounds able to inhibit this interaction constitute important potential leads towards the development of effective therapeutic agents. We recently described the discovery of a set of compounds able to bind (CUG) repeat RNA with significant selectivity and inhibit MBNL1 binding. Our proposed research centers on three Aims that will expand on this important initial result, and obtain compounds suitable for clinical development. First, we will determine the minimum binding peptide capable of maintaining selective (CUG) repeat RNA binding, and will explore the effect of peptide N-methylation on affinity. Second, we will employ the highest-affinity lead compound in a displacement-based high throughput screen for new (CUG) repeat-binding chemotypes. Finally, we will carry out a series of cellular assays to determine the ability of new compounds to inhibit (CUG) RNA - MBNL1 binding in a cellular context. PUBLIC HEALTH RELEVANCE: Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, affecting 1 in 8000 people. The disease is believed to result from the accumulation of a toxic RNA, termed a "CUG repeat", which sequesters a protein critical for proper cellular function. Building on a discovery made in our laboratory of a molecule able to bind CUG repeat RNA, we will carry out a series of experiments designed to yield a new molecule with higher activity and improved drug-like properties. The overall goal of the project will be to obtain at least one compound suitable for development as a therapeutic agent.