title: Precise small-molecule recognition of a toxic CUG RNA repeat expansion.
abstract: 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)expand reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)expin its natural context.
authors.affiliation: Departments of Chemistry and Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Rzuczek
authors.affiliation: Max Planck Florida Institute for Neuroscience, Jupiter, Florida, USA.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Colgan
authors.affiliation: Departments of Chemistry and Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nakai
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Sorbonne Universités UPMC Université Paris 06, INSERM, CNRS, Centre de Recherche en Myologie, Institut de Myologie, Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.affiliation: Max Planck Florida Institute for Neuroscience, Jupiter, Florida, USA.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yasuda
authors.affiliation: Departments of Chemistry and Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Matthew D
authors.identifier: 0000-0001-8486-1796
authors.initials: MD
authors.lastname: Disney
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D012313:RNA / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D012326:RNA Splicing / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects*
chemical_list: D054852:Small Molecule Libraries; D012313:RNA