title: Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1.
abstract: Myotonic dystrophy type 1 (DM1) is caused when an expanded r(CUG) repeat (r(CUG)(exp)) binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1) as well as other proteins. Previously, we reported that modularly assembled small molecules displaying a 6'-N-5-hexynoate kanamycin A RNA-binding module (K) on a peptoid backbone potently inhibit the binding of MBNL1 to r(CUG)(exp). However, these parent compounds are not appreciably active in cell-based models of DM1. The lack of potency was traced to suboptimal cellular permeability and localization. To improve these properties, second-generation compounds that are conjugated to a d-Arg(9) molecular transporter were synthesized. These modified compounds enter cells in higher concentrations than the parent compounds and are efficacious in cell-based DM1 model systems at low micromolar concentrations. In particular, they improve three defects that are the hallmarks of DM1: a translational defect due to nuclear retention of transcripts containing r(CUG)(exp); pre-mRNA splicing defects due to inactivation of MBNL1; and the formation of nuclear foci. The best compound in cell-based studies was tested in a mouse model of DM1. Modest improvement of pre-mRNA splicing defects was observed. These studies suggest that a modular assembly approach can afford bioactive compounds that target RNA.
authors.affiliation: Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Childs-Disney
authors.forename: Raman
authors.initials: R
authors.lastname: Parkesh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamori
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D031541:Fluorescence Resonance Energy Transfer; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000235:genetics; D016133:Polymerase Chain Reaction; D012313:RNA / Q000187:drug effects*; D012326:RNA Splicing
chemical_list: D000617:Aminoglycosides; D017931:DNA Primers; D012313:RNA