Macrocyclization of a ligand targeting a toxic RNA dramatically improves potency.

Macrocyclization of a ligand targeting a toxic RNA dramatically improves potency. Chembiochem. 2020 Jul 10;: Authors: Benhamou R, Vezina-Dawod S, Choudhary S, Wang KW, Meyer SM, Yildirim I, Disney M Abstract 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 10-fold 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 selectivity for the target, thereby inhibiting r(CUG)exp's toxic interaction with muscleblind-like 1 (MBNL1), and its superior cell permeability. Macrocyclization may prove an effective way to enhance the bioactivity of modularly assembled ligands targeting RNA. PMID: 32649032 [PubMed - as supplied by publisher]
Source: Chembiochem - Category: Biochemistry Authors: Tags: Chembiochem Source Type: research