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RNA–drug interactions

RNA as an off-target for FDA-approved drugs

Nature Chemistry volume 15, pages 1329–1331 (2023)Cite this article

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Medicinal chemistry efforts typically focus on drug–protein interactions and overlook RNA binding as a source of off-target pharmacology. Now, a new method has been developed to map the interactions of small-molecule drugs with RNA in cells and characterize how these interactions can exert functional effects.

Understanding both on- and off-target interactions is essential for drug development. Comprehensive information about how drug molecules function increases the chance of clinical trial success and lowers the risk of post-approval drug withdrawal due to unidentified off-target effects. Current mechanism-of-action studies typically focus on proteomic-based target engagement and selectivity, and largely overlook RNA as a target for small molecules. However, RNA has regulatory functions apart from coding for polypeptide sequences and can fold into structures that are targetable with small molecules1. For instance, libraries of druglike compounds have been shown to be good sources of ligands for RNA2, and the approval of risdiplam3 to treat spinal muscular atrophy validates RNA as a small-molecule drug target. Other studies have indicated that investigational drugs such as dovitinib4 and ataluren5 interact directly with RNA, highlighting the need to better understand RNA–ligand interactions in the drug development process. Current methods for mapping interactions between RNA and small molecules rely on the use of photoaffinity labelling or alkylators and can require high probe concentrations, long incubation times or ultraviolet irradiation, all of which can influence gene expression or result in damage, affecting their use in cells. Now, writing in Nature Chemistry, Kool and colleagues develop a new reactivity-based RNA profiling (RBRP) method for mapping transcriptome-wide small-molecule/RNA interactions in live cells and use this method to identify multiple functional off-target RNA–drug interactions6.

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Fig. 1: Reactivity-based RNA profiling of FDA-approved drugs reveals off-target transcriptome interactions that may contribute to side effects and dose-limiting toxicity.

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Authors and Affiliations

  1. Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA

    Christopher R. Fullenkamp & John S. Schneekloth Jr

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  1. Christopher R. Fullenkamp
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  2. John S. Schneekloth Jr
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Correspondence to John S. Schneekloth Jr.

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The authors declare no competing interests.

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Fullenkamp, C.R., Schneekloth, J.S. RNA as an off-target for FDA-approved drugs. Nat. Chem. 15, 1329–1331 (2023). https://doi.org/10.1038/s41557-023-01330-x

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