Macrocyclization of a Ligand Targeting a Toxic RNA Dramatically Improves Potency

Raphael I. Benhamou, Simon Vezina-Dawod, Shruti Choudhary, Kye Won Wang, Samantha M. Meyer, Ilyas Yildirim, Matthew D. Disney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageAmerican English
Pages (from-to)3229-3233
Number of pages5
Issue number22
StatePublished - 16 Nov 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Wiley-VCH GmbH


  • RNA
  • chemical biology
  • macrocycles
  • myotonic dystrophy
  • repeat expansion disorder


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