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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 agentsin situvia 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)^expin 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 viain situsynthesis and could be applied to other nucleic acid targets.

Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder that is inherited in an autosomal dominant manner. DM1 originates in a (CTG⋅CAG) repeat expansion in the 3’‐UTR of the dystrophia myotonic protein kinase (DMPK) gene on chromosome 19. One of the transcripts, r(CUG)^exp, is toxic in various ways. Herein we report a rationally designed small molecule with a thiazole peptidomimetic unit that can serve as a minor groove binder for the nucleic acid targets. This peptide unit linked to two triaminotriazine recognition units selectively binds to d(CTG)^expto inhibit the transcription process, and also targets r(CUG)^expselectively to improve representative DM1 pathological molecular features, including foci formation and pre‐mRNA splicing defects in DM1 model cells. As such, it represents a new structure type that might serve as a lead compound for future structure‐activity optimization.