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Accueil du site > Équipes > Molécules Bioactives > Thème Ligands d’Acides Nucléiques (Targeting of Nucleic Acids research group)

Thème Ligands d’Acides Nucléiques (Targeting of Nucleic Acids research group)

Research

We are a recently established research group that is focusing its activity on the design of new small-molecule ligands targeting biologically relevant RNAs that represent original and innovative therapeutic targets. All our projects aim at improving the fundamental understanding of selective interactions that could be formed between ligands and the target and at designing general rules for the rational design of selective RNA binders. These chemical tools are then applied to chemical biology and medicinal chemistry projects.

Interrelated areas of focus include :

1) Therapeutic innovations in antibiotics : focus on the targeting of toxin-antitoxin systems using small-molecule RNA binders

There is currently an urgent need for new antibiotics in order to overcome the steady emergence of multidrug-resistant bacteria and the associated human and economic cost. For the development of new antimicrobial agents, two major issues must be overcome : the difficulty to permeate bacterial membranes and the toxicity of compounds. Furthermore, the available number of specific targets remains restricted. All these issues led to a strong decrease in the efforts done toward the discovery of new antibiotics both in industry and in academia. In this context, the purpose of this project is the discovery of new antibiotics targeting original and so far unexploited targets : bacterial toxin-antitoxin (TA) systems. TA systems are small genetic elements composed of a toxin gene and its cognate antitoxin both coding for corresponding toxin and antitoxin products. The toxins of all known TA systems are proteins able to inhibit bacterial cell growth or lead to cell death, whereas the antitoxins are either proteins or small regulatory RNAs that neutralize the toxin. Here, we decided to target type I TA systems where the antitoxin is a non-coding RNA that binds to the messenger RNA (mRNA) coding for the toxin thus inhibiting its translation.

This project is performed in collaboration with Dr. Fabien Darfeuille at ARNA Laboratory in Bordeaux.

This project is supported by ANR-PRC grant (ANR-PRC ANR-17-CE18-0009, 2018-2021).

2) New epigenetic approaches in glioblastoma treatment

Glioblastoma multiforme (GBM) is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations, including GBM stem-like cells (GSCs) which are believed to contribute to tumor initiation and to be responsible for recurrence following initial response to therapies. We discovered various hits among our library of RNA ligands that are able to induce GSCs differentiation and to increase their sensitivity to current chemotherapies by interfering with GSCs miRNAs network. The development of various series of analogs in order to improve the biological activity, describe structure-activity relationships and identify the molecular mechanism of action are currently in progress.

This project is performed in collaboration with Dr. Thierry Virolle at the Institut de Biologie Valrose.

Each series of analogs is supported by different grants from ARC (Projet Fondation ARC 2017-2018), SATTSud-Est (Maturation 2017-2020) and Institut de Recherche Servier (2017-2020).

3) Targeting oncogenic microRNAs : toward new chemotherapies

We have designed and synthesized various new series of RNA ligands able to bind selectively to two precursors of oncogenic microRNAs (pre-miR-372 and pre-miR-373) involved in the proliferation and tumorigenesis of gastric adenocarcinoma. The development of a cell-free high-throughput assay allowed the selection of most promising compounds for intracellular studies. We identified compounds able to selectively inhibit the production of oncogenic miRNAs and inhibit cancer cells proliferation and restor normal mRNA translation.

We also applied the HTS assay to the screening of larger libraries. As an example, the screening of the Essential Library belonging to the French National Chemical library led to the discovery of polyamine derivatives as promising compounds able to interfere with the biogenesis of oncogenic miRNAs.

Publications

1. Staedel, C., Tran, T.P.A., Giraud, J., Darfeuille, F., Di Giorgio, A., Tourasse, N.J., Salin, F., Uriac, P., Duca, M. Modulation of oncogenic miRNA biogenesis using functionalized polyamines Scientific Reports 2018 Just Accepted

2. Vo, D.D., Duca, M. Design of multimodal small molecules targeting miRNAs biogenesis : synthesis and in vitro evaluation Methods Mol. Biol. 2017 1517, 137.

3. Di Giorgio, A., Tran, T.P.A., Duca, M. Small–molecule approaches toward the targeting of oncogenic microRNAs : roadmap fort he discovery of microRNAs modulators Future Med. Chem. 2016 8, 803.

4. Vo, D.D., Tran, T.P.A. Staedel, C., Benhida, R., Darfeuille, F., Di Giorgio, A., Duca, M. Oncogenic microRNAs biogenesis as a drug target : structure-activity relationship studies on novel aminoglycoside conjugates Chem. Eur. J. 2016 22, 5350.

5. Tran T.P.A., Vo D.D., Di Giorgio A., Duca M. Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis : old scaffolds for new perspectives in RNA targeting Bioorg. Med. Chem. 2015 23, 5344.

6. Vo D.D., Staedel C., Zehnacker L., Benhida R., Darfeuille F., Duca M. Targeting the production of oncogenic microRNAs with multimodal synthetic small molecules ACS Chem. Biol. 2014 9, 711.

4) Targeting of viral RNAs : applications to HIV-TAR RNA

We prepared various glycoconjugates containing artificial nucleobases, sugars and amino acids in order to target the stem-loop structure of TAR RNA. This led to compounds bearing antiviral activity in infected cells upon inhibition of transcription.

Publications

1. Joly J.P., Mata G., Eldin P., Briant L., Fontaine-Vive F., Duca M.*, Benhida R.* Artificial nucleobase-amino acid conjugates : a new class of TAR RNA binding agents Chem. Eur. J. 2014 20, 2071.

2. Duca, M., Malnuit, V., Barbault, F., Benhida, R. Design of novel RNA ligands that bind stem-bulge HIV-1 TAR RNA Chem. Commun. 2010 46, 6162.

5) Treating cancer as an infectious disease with antibiotics

Compelling evidence suggests that cancer stem cells (CSC) are the roots of current shortcomings in advanced and metastatic colorectal cancer treatment. CSC represents a minor subpopulation of tumor cells endowed with self-renewal and multi-lineage differentiation capacity which can escape from both conventional and targeted therapies (cetuximab, avastin), disseminate and seed metastasis. For that reason, Targeting CSC has become a major goal to design new therapeutic routes that may prevent tumor relapse and metastasis. Most drugs possess off-target effects that might provide substantial benefit for cancer treatment. Our recent work suggests that some antibiotics are able to interfere with stem-like properties -such as self-renewal- inherent to CSC phenotype. This project aims to determine whether these compounds can be used as adjuvant during the course of classic chemotherapy to target CSC and prevent disease recurrence and metastatic process.

The project is performed in collaboration with Dr. Alexandre DAVID at Institut de Génomique Fonctionnelle in Montpellier.

This work is supported by INCa grant (INCa PLBio 2017-160, 2018-2020)