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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
Summary
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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