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( 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 can be further augmented for functionality including degradation.