Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 14, Pages 7827-7839Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00558
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Funding
- National Institutes of Health [DP1-NS096898, R35-NS116846-01, F31-NS110269]
- Department of Defense Peer-Reviewed Medical Research Program [W81XWH-18-0718]
- Muscular Dystrophy Association [380467]
- Myotonic U.S. Fellowship Research Grant
- National Ataxia Foundation Fellowship Research Grant
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RNA repeat expansions are responsible for more than 30 incurable diseases. Among them is myotonic dystrophy type 1 (DM1), the most common form of adult on-set muscular dystrophy. DM1 is caused by an r(CUG) repeat expansion [r(CUG)(exp)] located in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase gene. This repeat expansion is highly structured, forming a periodic array of 5'CUG/3'GUC internal loop motifs. We therefore designed dimeric compounds that simultaneously bind two of these motifs by connecting two RNA-binding modules with peptoid linkers of different geometries and lengths. The optimal linker contains two proline residues and enhances compound affinity. Equipping this molecule with a bleomycin A5 cleaving module converts the simple binding compound into a potent allele-selective cleaver of r(CUG)(exp). This study shows that the linker in modularly assembled ligands targeting RNA can be optimized to afford potent biological activity.
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