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

A solid-phase DNA-encoded library (DEL) was studied for binding the RNA repeat expansion r(), 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() 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(). In DM1 patient-derived muscle cells, the compound specifically bound r() and allele-specifically eliminated r(), improving disease-associated defects. The approaches herein can be used to identify and optimize ligands and bind RNA that can be further augmented for functionality including degradation.