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Design of a bioactive small molecule that targets the myotonic dystrophy type 1 RNA via an RNA motif-ligand database and chemical similarity searching

Academic Article
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Overview

authors

  • Parkesh, R.
  • Childs-Disney, J. L.
  • Nakamori, M.
  • Kumar, A.
  • Wang, E.
  • Wang, T.
  • Hoskins, J.
  • Tran, T.
  • Housman, D.
  • Thornton, C. A.
  • Disney, Matthew

publication date

  • March 2012

journal

  • Journal of the American Chemical Society  Journal

abstract

  • Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3'-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5'CUG/3'GUC motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Sequestration of MBNL1 by expanded r(CUG) repeats causes splicing defects in a subset of pre-mRNAs including the insulin receptor, the muscle-specific chloride ion channel, sarco(endo)plasmic reticulum Ca(2+) ATPase 1, and cardiac troponin T. Based on these observations, the development of small-molecule ligands that target specifically expanded DM1 repeats could be of use as therapeutics. In the present study, chemical similarity searching was employed to improve the efficacy of pentamidine and Hoechst 33258 ligands that have been shown previously to target the DM1 triplet repeat. A series of in vitro inhibitors of the RNA-protein complex were identified with low micromolar IC(50)'s, which are >20-fold more potent than the query compounds. Importantly, a bis-benzimidazole identified from the Hoechst query improves DM1-associated pre-mRNA splicing defects in cell and mouse models of DM1 (when dosed with 1 mM and 100 mg/kg, respectively). Since Hoechst 33258 was identified as a DM1 binder through analysis of an RNA motif-ligand database, these studies suggest that lead ligands targeting RNA with improved biological activity can be identified by using a synergistic approach that combines analysis of known RNA-ligand interactions with chemical similarity searching.

subject areas

  • Databases, Factual
  • HeLa Cells
  • Humans
  • Ligands
  • Myotonic Dystrophy
  • RNA
  • RNA-Binding Proteins
  • Small Molecule Libraries
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Identity

PubMed Central ID

  • PMC3306011

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja210088v

PubMed ID

  • 22300544
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Additional Document Info

start page

  • 4731

end page

  • 4742

volume

  • 134

issue

  • 10

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