title: A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor.
abstract: Potent modulators of RNA function can be assembled in cellulo by using the cell as a reaction vessel and a disease-causing RNA as a catalyst. When designing small molecule effectors of function, a balance between permeability and potency must be struck. Low molecular weight compounds are more permeable whereas higher molecular weight compounds are more potent. The advantages of both types of compounds could be synergized if low molecular weight molecules could be transformed into potent, multivalent ligands by a reaction that is catalyzed by binding to a target in cells expressing a genetic defect. It was shown that this approach is indeed viable in cellulo. Small molecule modules with precisely positioned alkyne and azide moieties bind adjacent internal loops in r(CCUG)(exp), the causative agent of myotonic dystrophy type 2 (DM2), and are transformed into oligomeric, potent inhibitors of DM2 RNA dysfunction by a Huisgen 1,3-dipolar cycloaddition reaction, a variant of click chemistry.
authors.affiliation: The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, #3A1, Jupiter, FL (USA).
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Rzuczek
authors.forename: HaJeung
authors.initials: H
authors.lastname: Park
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
mesh_terms: D000215:Acylation; D000480:Alkynes / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D001483:Base Sequence; D002384:Catalysis; D061565:Cycloaddition Reaction; D006801:Humans; D007612:Kanamycin / Q000737:chemistry; D009223:Myotonic Dystrophy / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000480:Alkynes; D001386:Azides; C493663:MBNL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D007612:Kanamycin; D012313:RNA
keywords: RNA; chemical biology; drug design; medicinal chemistry; nucleic acids