Expanded DNA and RNA Trinucleotide Repeats in Myotonic Dystrophy Type 1 Select Their Own Multitarget, Sequence-Selective Inhibitors

• Published in: Biochemistry (Easton) 2020-09, Vol.59 (37), p.3463-3472
• Main Authors: Hagler, Lauren D, Luu, Long M, Tonelli, Marco, Lee, JuYeon, Hayes, Samuel M, Bonson, Sarah E, Vergara, J. Ignacio, Butcher, Samuel E, Zimmerman, Steven C
• Format: Article
• Language: English
• Subjects: Cells, Cultured; DNA - antagonists & inhibitors; DNA - genetics; DNA - metabolism; Humans; Myotonic Dystrophy - drug therapy; Myotonic Dystrophy - genetics; Myotonic Dystrophy - pathology; RNA - antagonists & inhibitors; RNA - genetics; RNA - metabolism; Small Molecule Libraries - pharmacology; Trinucleotide Repeat Expansion - drug effects; Trinucleotide Repeat Expansion - genetics
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/acs.biochem.0c00472

There are few methods available for the rapid discovery of multitarget drugs. Herein, we describe the template-assisted, target-guided discovery of small molecules that recognize d­(CTG) in the expanded d­(CTG·CAG) sequence and its r­(CUG) transcript that cause myotonic dystrophy type 1. A positive cross-selection was performed using a small library of 30 monomeric alkyne- and azide-containing ligands capable of producing >5000 possible di- and trimeric click products. The monomers were incubated with d­(CTG)16 or r­(CUG)16 under physiological conditions, and both sequences showed selectivity in the proximity-accelerated azide–alkyne [3+2] cycloaddition click reaction. The limited number of click products formed in both selections and the even smaller number of common products suggests that this method is a useful tool for the discovery of single-target and multitarget lead therapeutic agents.