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 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.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Chembiochem : a European journal of chemical biology
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
