title: A small molecule that targets r(CGG)(exp) and improves defects in fragile X-associated tremor ataxia syndrome.
abstract: The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is defining which chemical and RNA motif spaces interact specifically. Herein, we describe a bioactive small molecule probe that targets expanded r(CGG) repeats, or r(CGG)(exp), that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium binds the 5'CGG/3'GGC motifs in r(CGG)(exp) and disrupts a toxic r(CGG)(exp)-protein complex in vitro. Structure-activity relationship studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG)(exp). Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)(exp)-containing nuclear foci. This approach may establish a general strategy to identify lead ligands that target RNA while also providing a chemical probe to dissect the varied mechanisms by which r(CGG)(exp) promotes toxicity.
authors.affiliation: Department of Chemistry, The Kellogg School of Science and Engineering, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States. Disney@scripps.edu
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
authors.forename: Biao
authors.initials: B
authors.lastname: Liu
authors.forename: Wang-Yong
authors.initials: WY
authors.lastname: Yang
authors.forename: Chantal
authors.initials: C
authors.lastname: Sellier
authors.forename: Tuan
authors.initials: T
authors.lastname: Tran
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Childs-Disney
mesh_terms: D000818:Animals; D001259:Ataxia / Q000188:drug therapy*; D001667:Binding, Competitive / Q000187:drug effects; D019556:COS Cells; D002467:Cell Nucleus / Q000187:drug effects; D002522:Chlorocebus aethiops; D005600:Fragile X Syndrome / Q000188:drug therapy*; D011485:Protein Binding; D012313:RNA / Q000187:drug effects*; D012326:RNA Splicing; D012091:Repetitive Sequences, Nucleic Acid / Q000187:drug effects*; D054852:Small Molecule Libraries; D014202:Tremor / Q000188:drug therapy*
chemical_list: D054852:Small Molecule Libraries; D012313:RNA