Dynamic Covalent Template-Guided Screen for Nucleic Acid-Targeting Agents

Sarah B. Krueger, Steven C. Zimmerman

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Trinucleotide repeat diseases such as myotonic dystrophy type 1 (DM1) and Huntington's disease (HD) are caused by expanded DNA repeats that can be used as templates to synthesize their own inhibitors. Because it would be particularly advantageous to reversibly assemble multivalent nucleic acid-targeting agents in situ, we sought to develop a target-guided screen that uses dynamic covalent chemistry to identify multitarget inhibitors. We report the synthesis of a library of amine- or aldehyde-containing fragments. The assembly of these fragments led to a diverse set of hit combinations that was confirmed by matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) in the presence of DM1 and HD repeat sequences. Of interest for both diseases, the resulting hit combinations inhibited transcription selectively and in a cooperative manner in vitro, with inhibitory concentration (IC50) values in the micromolar range. This dynamic covalent library and screening approach could be applied to identify compounds that reversibly assemble on other nucleic acid targets.

Original languageEnglish
Pages (from-to)12417-12426
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number18
StatePublished - 22 Sep 2022
Externally publishedYes

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine


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