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

ABSTRACT: Myotonic dystrophy type 1 (DM1) is caused by a highly structured RNA repeat expansion, r(CUG)^exp, harbored in the 3' untranslated region (3' UTR) of dystrophia myotonica protein kinase (DMPK) 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)^expin vitro, affording perimidin-2-amine diazirine (1) that bound to r(CUG)^exp. The interactions between the small molecule and RNA were further studied by nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. Binding of 1 in DM1 myotubes was profiled transcriptome-wide, identifying 12 transcripts including DMPK that were bound by 1</

SUBMITTER: Gibaut QMR 

PROVIDER: S-EPMC10375898 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature