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Pervasive transcriptome interactions of protein-targeted drugs

Linglan Fang1, Willem A Velema1, Yujeong Lee1

  • 1Department of Chemistry, Stanford University, Stanford, CA, USA.

Nature Chemistry
|August 31, 2023
PubMed

Insights

Protein-targeted drugs can interact with the human transcriptome, causing unintended biological effects. This study introduces a new method to identify these RNA interactions, potentially improving drug safety and efficacy.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Genomics

Background:

  • Off-target drug toxicity leads to significant health and economic burdens.
  • While protein interactions are studied, intracellular RNA interactions as off-targets remain under-explored.
  • Understanding RNA interactions is crucial for assessing drug safety and efficacy.

Purpose of the Study:

  • To develop and apply a novel reactivity-based RNA profiling method.
  • To investigate in vivo transcriptome interactions of FDA-approved small-molecule drugs.
  • To assess the potential of RNA off-target binding to contribute to drug toxicity.

Main Methods:

  • Development of a reactivity-based RNA profiling methodology.
  • In vivo application of the method to study drug-transcriptome interactions.
  • Analysis of RNA loci associated with protein binding and structural changes.

Main Results:

  • Protein-targeted drugs extensively interact with the human transcriptome.
  • These interactions can lead to unintended biological effects on RNA functions.
  • Off-target binding frequently occurs at RNA sites involved in protein interactions and structural modifications.

Conclusions:

  • Drugs approved for protein targets can pervasively interact with RNA.
  • Characterizing drug-transcriptome interactions can reveal potential toxicity mechanisms.
  • Assessing RNA interactions may enhance drug specificity and prevent clinical failures.

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