RNA functional modulation by Mitoxantrone via RNA structural ensemble repartitioning.
basic_science · Level V
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- Record sourced from PubMed, PMID 41872169.
- Also identified by DOI 10.1038/s41467-026-70801-9.
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Abstract
Targeting RNA with small molecules offers a strategy to modulate gene expression at undruggable targets. Traditional screens favor thermodynamically stable, low-entropy RNA motifs with defined conformations, yet these provide limited energetic leverage for functional modulation. Many RNAs instead sample dynamic structural ensembles that small molecules can repartition. Using group I self-splicing introns as a model, we identified the antineoplastic drug Mitoxantrone as a competitive inhibitor of RNA self-splicing (IC<sub>50</sub> = 4.3 μM) that stabilizes the native conformation of the T4 td intron. Structure-activity analysis showed that the anthraquinone scaffold alone is insufficient, and basic amine-containing side chains are required for RNA structural modulation. Transcriptome-wide chemical probing in human cells revealed preferential binding to GC-rich structured regions, although only a subset showed structural change. Furthermore, global analysis of 5' UTR ensembles showed altered structural heterogeneity and translation, demonstrating functional repartitioning of RNA conformational landscapes.