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

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.