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<p>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 <i>td</i> 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.</p>

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RNA functional modulation by Mitoxantrone via RNA structural ensemble repartitioning

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月23日

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  • Chundan Zhang,
  • Ivana Borovská,
  • Teona Iobashvili,
  • Edoardo Morandi,
  • Marta Lionnez,
  • Oluwatosin S. Olayinka,
  • Rinse de Boer,
  • Massimiliano Clamer,
  • Martin D. Witte,
  • Klaus Pors,
  • John S. Schneekloth Jr.,
  • Danny Incarnato

摘要

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 (IC50 = 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.