Open AccessMassively Parallel Optimization of the Linker Domain in Small Molecule Dimers Targeting a Toxic r(CUG) Repeat Expansion
Author(s) -
Simon VézinaDawod,
Alicia J. Angelbello,
Sonal Choudhary,
Kye Won Wang,
Ilyas Yildirim,
Matthew D. Disney
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00027
Subject(s) - linker , rna , small molecule , cleavage (geology) , myotonic dystrophy , computational biology , massively parallel , biophysics , chemistry , biology , combinatorial chemistry , genetics , biochemistry , gene , computer science , paleontology , fracture (geology) , parallel computing , operating system
RNA contributes to disease pathobiology and is an important therapeutic target. The downstream biology of disease-causing RNAs can be short-circuited with small molecules that recognize structured regions. The discovery and optimization of small molecules interacting with RNA is, however, challenging. Herein, we demonstrate a massively parallel one-bead-one-compound methodology, employed to optimize the linker region of a dimeric compound that binds the toxic r(CUG) repeat expansion [r(CUG) exp ] causative of myotonic dystrophy type 1 (DM1). Indeed, affinity selection on a 331,776-member library allowed the discovery of a compound with enhanced potency both in vitro (10-fold) and in DM1-patient-derived myotubes (5-fold). Molecular dynamics simulations revealed additional interactions between the optimized linker and the RNA, resulting in ca. 10 kcal/mol lower binding free energy. The compound was conjugated to a cleavage module, which directly cleaved the transcript harboring the r(CUG) exp and alleviated disease-associated defects.