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Nat Chem Biol. 2017 Feb;13(2):188-193. doi: 10.1038/nchembio.2251. Epub 2016 Dec 12.

Precise small-molecule recognition of a toxic CUG RNA repeat expansion.

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Departments of Chemistry and Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.
Max Planck Florida Institute for Neuroscience, Jupiter, Florida, USA.
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
Sorbonne Universités UPMC Université Paris 06, INSERM, CNRS, Centre de Recherche en Myologie, Institut de Myologie, Paris, France.


Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)exp) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG)exp. In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG)exp and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)exp in its natural context.

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