The development of on-target, self-assembling therapeutic agents has gained renewed interest recently. Herein, r(CUG)16, a model for the toxic expanded CUG RNA that causes myotonic dystrophy type 1 (DM1), is used as a template to selectively couple small molecules. A library of alkyne- and azide-containing ligands, capable of producing more than 5000 compounds, was incubated in the presence of r(CUG)16 under physiological conditions. The r(CUG)16 accelerates the alkyne-azide [3+2]-cycloaddition by bringing suitable clickable partners in close proximity, whereas other RNA sequences, such as r(CCUG)8 and tRNA, are inactive. The limited number of click products formed indicates that this dynamic selection is very useful for the discovery of therapeutic agents that target the DM1 toxic RNA. Beyond being a powerful strategy for discovering tighter binding leads, the in situ target-guided synthesis can be a therapeutic approach, because it can avoid the poor uptake of high molecular weight agents.

On-target synthesis and selection of modular therapeutic agents for myotonic dystrophy

251st National Meeting (2016)

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