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

Content Provider	PubMed Central
Author	Yang, Wang-yong Gao, Rui Southern, Mark Sarkar, Partha S. Disney, Matthew D.
Copyright Year	2016
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.
Related Links	http://dx.doi.org/10.1038/ncomms11647
Starting Page	11647
File Format	PDF
ISSN	20411723
e-ISSN	20411723
Journal	Nature Communications
Volume Number	7
Language	English
Publisher	Nature Publishing Group
Publisher Date	2016-06-01
Access Restriction	Open
Rights Holder	Nature Publishing Group
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Physics and Astronomy(all) Chemistry(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Chemistry Physics and Astronomy Biochemistry, Genetics and Molecular Biology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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