Dr. Maria Duca is head of Targeting of Nucleic Acids research group in the Institute of Chemistry of Nice (Université Côte d’Azur – CNRS). After undergraduate studies in Pharmacy and Medicinal Chemistry (Faculty of Pharmacy, University of Bologna, Italy), she obtained her PhD in Molecular Biochemistry under the supervision of Dr. Paola B. Arimondo (National Natural History Museum, Paris, France) working on topoisomerase II inhibitors. A 2-year post-doctoral training in Sydney Hecht’s lab (Department of Chemistry, University of Virginia, USA) allowed her to pursue the study of nucleic acids working on targeted protein mutagenesis. After CNRS recruitment as a Research Scientist in 2007, her research activities focus on the targeting of non-coding RNAs using synthetic small molecules toward innovative therapeutic approaches both for anticancer and antimicrobial applications.
Design and implementation of small-molecule RNA binders for anticancer and antimicrobial therapies
Non-coding RNAs recently raised as a major drug target and one of the greatest challenges of current medicinal chemistry (1). Various approaches have been described to target biologically relevant RNAs but the use of small molecules is one of the most promising for therapeutic applications and recent approval of Risdiplam as a mRNA splicing regulator for the treatment of SMA further underlined the potential of RNA targeting in clinic (2). During recent years, we focused our activities on the targeting of various non-coding RNAs such as viral, bacterial or oncogenic RNAs with a particular attention toward microRNAs (miRNAs). These are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human cancers, thus being oncogenic and that the inhibition of oncogenic miRNAs (defined as the blocking of miRNAs’ production or function) would find application in the therapy of different types of cancer in which these miRNAs are implicated (3).
Our work aims at the development of original small-molecule drugs targeting specific oncogenic miRNAs production as illustrated in (4). Toward this aim, we perform both the synthesis of new RNA ligands and the screening of compounds libraries. Both approaches are based on a high throughput in vitro assays and demonstrated to be successful in identifying compounds able to interfere with the biogenesis of oncogenic miRNAs in a selective manner at the intracellular level. Thanks to these works, we demonstrated that it is possible to inhibit miRNAs production using synthetic small molecules and that this kind of approach could be applied in future anticancer therapies. The chemical tools developed in these different projects could thus find extremely important applications as chemical biology tools for important clinical applications not only in anticancer therapies but also in target validation programs and for the discovery of new antimicrobials.
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