Quentin M. R. Gibaut; Yoshihiro Akahori; Jessica A. Bush; Amirhossein Taghavi; Toru Tanaka; Haruo Aikawa; Lucas S. Ryan; Brian M. Paegel; Matthew D. Disney
J. Am. Chem. Soc., 2022, 144(48), 21972-21979
https://doi.org/10.1021/jacs.2c08883

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 can be further augmented for functionality including degradation.