Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10

Wang-Yong Yang, Rui Gao, Mark Southern, Partha S. Sarkar and Matthew D. Disney ()
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Wang-Yong Yang: The Scripps Research Institute, Scripps Florida
Rui Gao: Mitchell Center for Neurodegenerative Disorders, Neuroscience and Cell Biology, University of Texas Medical Branch
Mark Southern: Informatics Core, The Scripps Research Institute, Scripps Florida
Partha S. Sarkar: Mitchell Center for Neurodegenerative Disorders, Neuroscience and Cell Biology, University of Texas Medical Branch
Matthew D. Disney: The Scripps Research Institute, Scripps Florida

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells.

Date: 2016
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DOI: 10.1038/ncomms11647

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