Key result
Macrocyclization of a linear dimeric ligand targeting the toxic RNA repeat expansion in myotonic dystrophy type 1 yielded a compound ten times more potent in patient-derived muscle cells.
Why the study?
RNA molecules contribute to and cause many human diseases, but discovering bioactive small-molecule ligands targeting RNA structure is challenging.
Does a macrocyclic compound improve potency against DM1-associated defects compared to a linear dimeric ligand in patient-derived myotubes?
Does a macrocyclic compound improve potency against DM1-associated defects compared to a linear dimeric ligand in patient-derived myotubes?
Effect estimate: 10 times more potent
Macrocyclization of a linear dimeric ligand targeting toxic RNA significantly improves its potency, affinity, selectivity, and cell permeability in models of myotonic dystrophy type 1.
Macrocyclization may enhance RNA-targeted ligands for DM1 in vitro; leaves open translation to cellular or in vivo models.
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.
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Benhamou et al. (2020) studied Myotonic dystrophy type 1 (DM1). Macrocyclic ligand vs. Linear dimeric ligand was evaluated on Improvement of DM1-associated defects in cells (10 times more potent). Macrocyclization of a linear dimeric ligand targeting the toxic RNA repeat expansion in myotonic dystrophy type 1 yielded a compound ten times more potent in patient-derived muscle cells.
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