RNA molecules both contribute to and are causative of many human diseases. One method to perturb RNA function is to target its structure with small molecules. However, discovering bioactive ligands for RNA targets is challenging. Here, we show that the bioactivity of a linear dimeric ligand that inactivates the RNA trinucleotide repeat expansion that causes myotonic dystrophy type 1 [DM1; r(CUG)exp] can be improved by macrocyclization. Indeed, the macrocyclic compound is ten times more potent than the linear compound for improving DM1-associated defects in cells, including in patient-derived myotubes (muscle cells). This enhancement in potency is due to the macrocycle's increased affinity and selectively for the target, which inhibit r(CUG)exp’s toxic interaction with muscleblind-like 1 (MBNL1), and its superior cell permeability. Macrocyclization could prove to be an effective way to enhance the bioactivity of modularly assembled ligands targeting RNA.
Bibliographical noteFunding Information:
We thank Dr. J. L. Childs‐Disney for help writing this manuscript and the agencies that funded this work including the National Institutes of Health (DP1‐NS096898 and R35MS116846 to M.D.D), the Muscular Dystrophy Association (grant 380467 to M.D.D.), the Myotonic US Fellowship Research grant (to R.I.B. and S.C.), and the Fonds de Recherche du Québec – Nature et Technologies (B3X scholarship to S.V.D.).
© 2020 Wiley-VCH GmbH
- chemical biology
- myotonic dystrophy
- repeat expansion disorder