Open AccessVersatile Target-Guided Screen for Discovering Bidirectional Transcription Inhibitors of a Trinucleotide Repeat Disease
Author(s) -
Lauren D. Hagler,
Sarah Krueger,
Long M. Luu,
Amie N. Lanzendorf,
Niya L. Mitchell,
Jessica Vergara,
L. Daniel Curet,
Steven C. Zimmerman
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00064
Subject(s) - trinucleotide repeat expansion , myotonic dystrophy , nucleic acid , transcription (linguistics) , click chemistry , computational biology , biology , rna , genetics , microbiology and biotechnology , chemistry , combinatorial chemistry , gene , linguistics , allele , philosophy
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 IC 50 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.