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Targeting the r(CGG) repeats that cause FXTAS with modularly assembled small molecules and oligonucleotides

Academic Article
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Overview

authors

  • Tran, T.
  • Childs-Disney, J. L.
  • Liu, B.
  • Guan, L. R.
  • Rzuczek, S.
  • Disney, Matthew

publication date

  • April 2014

journal

  • ACS Chemical Biology  Journal

abstract

  • We designed small molecules that bind the structure of the RNA that causes fragile X-associated tremor ataxia syndrome (FXTAS), an incurable neuromuscular disease. FXTAS is caused by an expanded r(CGG) repeat (r(CGG)(exp)) that inactivates a protein regulator of alternative pre-mRNA splicing. Our designed compounds modulate r(CGG)(exp) toxicity in cellular models of FXTAS, and pull-down experiments confirm that they bind r(CGG)(exp) in vivo. Importantly, compound binding does not affect translation of the downstream open reading frame (ORF). We compared molecular recognition properties of our optimal compound to oligonucleotides. Studies show that r(CGG)(exp)'s self-structure is a significant energetic barrier for oligonucleotide binding. A fully modified 2'-OMethyl phosphorothioate is incapable of completely reversing an FXTAS-associated splicing defect and inhibits translation of the downstream ORF, which could have deleterious effects. Taken together, these studies suggest that a small molecule that recognizes structure may be more well suited for targeting highly structured RNAs that require strand invasion by a complementary oligonucleotide.

subject areas

  • Animals
  • Ataxia
  • Blotting, Western
  • COS Cells
  • Cercopithecus aethiops
  • Drug Delivery Systems
  • Fragile X Syndrome
  • Gene Expression Regulation
  • Inhibitory Concentration 50
  • Oligonucleotides
  • Polymerase Chain Reaction
  • Protein Binding
  • Small Molecule Libraries
  • Tremor
  • Trinucleotide Repeat Expansion
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Identity

PubMed Central ID

  • PMC4287843

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb400875u

PubMed ID

  • 24506227
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Additional Document Info

start page

  • 904

end page

  • 912

volume

  • 9

issue

  • 4

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