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Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1

Academic Article
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Overview

authors

  • Childs-Disney, J. L.
  • Parkesh, R.
  • Nakamori, M.
  • Thornton, C. A.
  • Disney, Matthew

publication date

  • December 2012

journal

  • ACS Chemical Biology  Journal

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.

subject areas

  • Aminoglycosides
  • Animals
  • Base Sequence
  • DNA Primers
  • Fluorescence Resonance Energy Transfer
  • In Situ Hybridization, Fluorescence
  • Mice
  • Myotonic Dystrophy
  • Polymerase Chain Reaction
  • RNA
  • RNA Splicing
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Identity

PubMed Central ID

  • PMC3528830

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb3001606

PubMed ID

  • 23130637
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Additional Document Info

start page

  • 1984

end page

  • 1993

volume

  • 7

issue

  • 12

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