A small molecule that targets r(CGG)(exp) and improves defects in fragile X-associated tremor ataxia syndrome

The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is defining which chemical and RNA motif spaces interact specifically. Herein, we descr...

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Bibliographic Details
Published in:ACS chemical biology 2012-10, Vol.7 (10), p.1711
Main Authors: Disney, Matthew D, Liu, Biao, Yang, Wang-Yong, Sellier, Chantal, Tran, Tuan, Charlet-Berguerand, Nicolas, Childs-Disney, Jessica L
Format: Article
Language:English
Subjects:
Animals
Ataxia - drug therapy
Binding, Competitive - drug effects
Cell Nucleus - drug effects
Cercopithecus aethiops
COS Cells
Fragile X Syndrome - drug therapy
Protein Binding
Repetitive Sequences, Nucleic Acid - drug effects
RNA - drug effects
RNA Splicing
Small Molecule Libraries
Tremor - drug therapy
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Summary:The development of small molecule chemical probes or therapeutics that target RNA remains a significant challenge despite the great interest in such compounds. The most significant barrier to compound development is defining which chemical and RNA motif spaces interact specifically. Herein, we describe a bioactive small molecule probe that targets expanded r(CGG) repeats, or r(CGG)(exp), that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium binds the 5'CGG/3'GGC motifs in r(CGG)(exp) and disrupts a toxic r(CGG)(exp)-protein complex in vitro. Structure-activity relationship studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG)(exp). Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)(exp)-containing nuclear foci. This approach may establish a general strategy to identify lead ligands that target RNA while also providing a chemical probe to dissect the varied mechanisms by which r(CGG)(exp) promotes toxicity.
ISSN:1554-8937
DOI:10.1021/cb300135h