Versatile Target-Guided Screen for Discovering Bidirectional Transcription Inhibitors of a Trinucleotide Repeat Disease

Lauren D. Hagler, Sarah B. Krueger, Long M. Luu, Amie N. Lanzendorf, Niya L. Mitchell, J. Ignacio Vergara, L. Daniel Curet, Steven C. Zimmerman

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Myotonic dystrophy type 1 originates from d(CTG·CAG) repeats that undergo aberrant expansion during normal processing because the d(CTG) repeat forms stable hairpin structures. Bidirectional transcription of d(CTG·CAG) yields two RNA transcripts that undergo repeat-associated non-ATG (RAN) translation to form homopolymeric proteins. Thus, both the r(CUG) transcript and the r(CAG) transcript are known to be toxic. We report a pairwise fragment-based, target-guided approach to screen for proximity-induced click dimers formed on the nucleic acid template. This screen uses an azide/alkyne clickable fragment library of nucleic acid-binding ligands incubated in parallel, pairwise reactions as an alternative to our previously reported one-pot screening method. MALDI-TOF mass spectroscopy was used to detect template assisted click products. Hit compounds inhibited the in vitro transcription of d(CTG·CAG)90 bidirectionally with IC50 values in the low micromolar range. This approach may be broadly applicable to other trinucleotide repeat diseases and in targeting other disease-associated nucleic acid sequences.

Original languageEnglish
Pages (from-to)935-940
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume12
Issue number6
DOIs
StatePublished - 10 Jun 2021
Externally publishedYes

Keywords

  • Bidirectional transcription
  • Myotonic dystrophy type 1
  • Targeted-guided screen
  • Trinucleotide repeat disease

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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