Small molecule targeting of nucleic acids has come into focus as a therapeutic strategy for diseases such as myotonic dystrophy type 1 (DM1), a trinucleotide repeat disease characterized by its RNA gain-of-function mechanism. Herein, we report a novel template-selected, reversible assembly of therapeutic agents in situ via aldehyde-amine condensation. A library of rationally designed small molecule targeting agents (fragments) containing aldehyde or amine functionality was synthesized and screened. The selective assembly of fragments on template was confirmed by MALDI-MS in the presence of DM1- and Huntington’s Disease (HD)-relevant nucleic acid sequences. Of interest for both DM1 and HD, the resulting hit combinations of aldehyde and amine inhibited the formation of toxic RNA in vitro in a cooperative manner and rescued mis-splicing in DM1 model cells. This reversible template-selected assembly is a promising strategy to achieve cell permeability and multivalent targeting via in situ synthesis.

Template selected, reversible assembly of therapeutic agents for Myotonic dystrophy type 1

ACS Spring 2022

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