title: Targeting the r(CGG) repeats that cause FXTAS with modularly assembled small molecules and oligonucleotides.
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.
authors: Department of Chemistry, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #3A1, Jupiter, Florida 33458, United States.
authors: Tuan
authors: T
authors: Tran
authors: Jessica L
authors: JL
authors: Childs-Disney
authors: Biao
authors: B
authors: Liu
authors: Lirui
authors: L
authors: Guan
authors: Suzanne
authors: S
authors: Rzuczek
authors: Matthew D
authors: MD
authors: Disney
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics*; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D016503:Drug Delivery Systems; D005600:Fragile X Syndrome / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology; D014202:Tremor / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D009841:Oligonucleotides; D054852:Small Molecule Libraries