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Small molecule approaches to targeting RNA

Nature Reviews Chemistry volume 8, pages 120–135 (2024)Cite this article

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Abstract

The development of innovative methodologies to identify RNA binders has attracted enormous attention in chemical biology and drug discovery. Although antibiotics targeting bacterial ribosomal RNA have been on the market for decades, the renewed interest in RNA targeting reflects the need to better understand complex intracellular processes involving RNA. In this context, small molecules are privileged tools used to explore the biological functions of RNA and to validate RNAs as therapeutic targets, and they eventually are to become new drugs. Despite recent progress, the rational design of specific RNA binders requires a better understanding of the interactions which occur with the RNA target to reach the desired biological response. In this Review, we discuss the challenges to approaching this underexplored chemical space, together with recent strategies to bind, interact and affect biologically relevant RNAs.

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Fig. 1: Historical view of RNA ligands as marketed drugs.
Fig. 2: RNA binders based on aminoglycoside structure.
Fig. 3: RNA binders targeting secondary structures.
Fig. 4: NMR and SHAPE methodologies for RNA structure determination.
Fig. 5: Achieving RNA binding with additional functionalities.

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Acknowledgements

We thank the Italian Institute of Technology (IIT) and Université Côte d’Azur for the financial support to M.P. as PhD fellowship. We also thank BoostUrCareer COFUND project with Région PACA and European Union’s Horizon 2020 research and innovation programme under grant agreement no. 847581 for PhD fellowship to S.K. and the National Center for Gene Therapy and Drugs based on RNA Technology project (CN00000041) funded by European Union’s NextGenerationEU PNRR MUR - M4C2 – programme (CUP J33C22001130001).

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  1. These authors contributed equally: Sandra Kovachka, Marc Panosetti.

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  1. Université Côte d’Azur, CNRS, Institute of Chemistry of Nice, Nice, France

    Sandra Kovachka, Marc Panosetti, Stéphane Azoulay, Audrey Di Giorgio & Maria Duca

  2. Molecular Medicine Research Line, Istituto Italiano di Tecnologia (IIT), Genoa, Italy

    Marc Panosetti & Benedetto Grimaldi

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All authors researched data for the article. M.D., S.A. and A.D.G. contributed substantially to the discussion of the content. S.K. and M.P. contributed substantially to the illustrations of the article. M.D. wrote the article. All authors reviewed and edited the manuscript before submission.

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Kovachka, S., Panosetti, M., Grimaldi, B. et al. Small molecule approaches to targeting RNA. Nat Rev Chem 8, 120–135 (2024). https://doi.org/10.1038/s41570-023-00569-9

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