Design, synthesis and evaluation of small-molecule RNA binders: scope and applications

Maria Duca

Université Côte d’Azur, ICN, CNRS, Nice, France, maria.duca@univ-cotedazur.fr

RNA is one of the most intriguing and promising biological targets for the discovery of innovative drugs in a large number of pathologies and various biologically relevant RNAs that could serve as drug targets have already been identified (1). Among the most important ones, it is worth to mention prokaryotic ribosomal RNA which is the target of a number of currently employed antibiotics, viral RNAs such as TAR, RRE and DIS RNA of HIV-1 or oncogenic microRNAs that are tightly involved in the development and progression of various cancers. However, difficulties in the rational design of strong and specific smallmolecule ligands renders this kind of molecules relatively rare.

During the last fifteen years we devoted our research activities to the design, synthesis and evaluation of original small molecules as binders of non-coding RNAs for anticancer, antiviral and antimicrobial applications (2). This led us not only to the development of synthetic pathways to obtain new compounds selective for the biological target, but also to bioactive molecules able to induce the desired biological effect in cells (Figure 1). Results obtained in the field of targeting oncogenic microRNAs in cancer as well as the validation of new targets for antibiotic discovery will be presented illustrating the wide applications that the field of targeting RNAs with small molecules could have.

Références

(1) Kovachka S, Panosetti M, Grimaldi B, Azoulay S, Di Giorgio A, Duca M. Small molecule approaches to targeting RNA. Nature Rev. Chem. 2024, 8, 120.

(2) a) Maucort, C., Bonnet, M., Ortuno, J.C., Tucker, G., Quissac, E., Verreault, M., Azoulay, S., Di Giorgio, C., Di Giorgio, A., Duca, M. Synthesis of bleomycin-inspired RNA ligands targeting the biogenesis of oncogenic miRNAs. J. Med. Chem. 2023,66, 10639; b) Scheheoleva I., Fernandez-Remacha, D., Estrada-Tejedor, R., Duca, M., Michelet, V. De novo design of premiR-21 maturation inhibitors: synthesis and activity assessment. Chem. Eur. J. 2023, 29, e202301807; c) Tran, T.P.A., Poulet, S., Pernak, M., Rayar, A., Azoulay, S., Di Giorgio A., Duca, M. Development of 2-deoxystreptamine-nucleobase conjugates for the inhibition of oncogenic miRNAs production. RSC Med. Chem. 2022, 13, 311; d) Martin, C. Bonnet, M., Patino, N., Azoulay, S., Di Giorgio A., Duca, M. Design, synthesis and evaluation of neomycin-imidazole conjugates for RNA cleavage ChemPlusChem 2022, 87, e202200250; e) Maucort, C., Vo, D.D., Aouad, S., Charrat, C., Azoulay, S., Di Giorgio, A., Duca, M. Design and implementation of synthetic RNA binders for the inhibition of miR-21 biogenesis. ACS Med. Chem. Lett. 2021, 12, 899; f) Vo, D.D., Becquart, C., Tran, T.P.A., Di Giorgio, A., Darfeuille, F., Staedel, C., Duca, M. Building of neomycinnucleobase-amino acid conjugates for the inhibition of oncogenic miRNAs biogenesis. Org. Biomol. Chem. 2018, 16, 6262.

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