Fragment-based drug discovery and target-guided synthesis represent two strategies for developing novel therapeutics for RNA-mediated diseases. We have incorporated the major components of these strategies along with the use of click-chemistry to develop a biomolecular screening assay for RNA and DNA binding ligands, whereby the nucleic acid target synthesizes its own inhibitor. Thus, this strategy can be used to find single- or multi-target agents for a number of diseases. We have studied myotonic dystrophy type 1 (DM1) as a model disease. We first synthesized a compound library of DNA- and RNA-binding ligands with reactive azide and alkyne functionalities. These compounds were incubated with d(CTG) and r(CUG) repeat-containing targets. By this method, we have discovered several new ligands combining multiple binding fragments that can undergo a proximity-induced, template-assisted click reaction on the relevant target without the use of a catalyst. Further, we have begun to assess the viability of this strategy as a therapeutic approach in cells to change phenotypic outcomes consistent with DM1 and overcome challenges associated with cell permeability. Ultimately, we hope to find a novel therapeutic strategy or ligands that can be furthered advanced into animal models.

Template-assisted click chemistry as a therapuetic strategy for myotonic dystrophy type 1 (DM1)

2019 Fall National Meeting

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