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Transcriptome-Wide Studies of RNA-Targeted Small Molecules Provide a Simple and Selective r(CUG) Degrader in Myotonic Dystrophy. | LitMetric

AI Article Synopsis

Article Abstract

Myotonic dystrophy type 1 (DM1) is caused by a highly structured RNA repeat expansion, r(CUG), harbored in the 3' untranslated region (3' UTR) of dystrophia myotonica protein kinase () mRNA and drives disease through a gain-of-function mechanism. A panel of low-molecular-weight fragments capable of reacting with RNA upon UV irradiation was studied for cross-linking to r(CUG), affording perimidin-2-amine diazirine () that bound to r(CUG). The interactions between the small molecule and RNA were further studied by nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. Binding of in DM1 myotubes was profiled transcriptome-wide, identifying 12 transcripts including DMPK that were bound by . Augmenting the functionality of with cleaving capability created a chimeric degrader that specifically targets r(CUG) for elimination. The degrader broadly improved DM1-associated defects as assessed by RNA-seq, while having limited effects on healthy myotubes. This study (i) provides a platform to investigate molecular recognition of ligands directly in disease-affected cells; (ii) illustrates that RNA degraders can be more specific than the binders from which they are derived; and (iii) suggests that repeating transcripts can be selectively degraded due to the presence of multiple ligand binding sites.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375898PMC
http://dx.doi.org/10.1021/acscentsci.2c01223DOI Listing

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