Selective and Reversible Ligand Assembly on the DNA and RNA Repeat Sequences in Myotonic Dystrophy

Small molecule targeting of DNA and RNA sequences has come into focus as a therapeutic strategy for diseases such as myotonic dystrophy type 1 (DM1), a trinucleotide repeat disease characterized by RNA gain‐of‐function. Herein, we report a novel template‐selected, reversible assembly of therapeutic agents in situ via aldehyde‐amine condensation. Rationally designed small molecule targeting agents functionalized with either an aldehyde or an amine were synthesized and screened against the target nucleic acid sequence. The assembly of fragments was confirmed by MALDI‐MS in the presence of DM1‐relevant nucleic acid sequences. The resulting hit combinations of aldehyde and amine inhibited the formation of r(CUG)exp in vitro in a cooperative manner at low micromolar levels and rescued mis‐splicing defects in DM1 model cells. This reversible template‐selected assembly is a promising approach to achieve cell permeable and multivalent targeting via in situ synthesis and could be applied to other nucleic acid targets. Small molecules that selectively bind to and reversibly assemble on the DNA and RNA sequences that are the causative agent of myotonic dystrophy type 1 (DM1) were developed. The combination of dialdehyde and diamine inhibited the formation of toxic RNA in vitro and rescued mis‐splicing in DM1 model cells.