Study of an RNA-Focused DNA-Encoded Library Informs Design of a Degrader of a r(CUG) Repeat Expansion.

ABSTRACT: A solid-phase DNA-encoded library (DEL) was studied for binding the RNA repeat expansion r(CUG)^exp, the causative agent of the most common form of adult-onset muscular dystrophy, myotonic dystrophy type 1 (DM1). A variety of uncharged and novel RNA binders were identified to selectively bind r(CUG)^exp by using a two-color flow cytometry screen. The cellular activity of one binder was augmented by attaching it with a module that directly cleaves r(CUG)^exp. In DM1 patient-derived muscle cells, the compound specifically bound r(CUG)^exp and allele-specifically eliminated r(CUG)^exp, improving disease-associated defects. The approaches herein can be used to identify and optimize ligands and bind RNA that ca

SUBMITTER: Gibaut QMR 

PROVIDER: S-EPMC9878440 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature