Targeting of Nucleic Acids

Targeting of Nucleic Acids


Group leader: Maria DUCA


Research group new

RNA represents a major biological target for future drug development, because it is involved in a wide number of biological processes, such as transcription, translation or catalysis and more importantly it is essential for the regulation of gene expression. Most biologically relevant RNAs bear a three-dimensional structure containing single-stranded regions (loops and bulges) associated to double-stranded regions that offers the possibility for selective/specific binding interactions with proteins and small-molecule ligands. The main goal of our research activities is to design and synthesize new RNA ligands bearing both strong affinity and high selectivity for a biologically relevant RNA target and to study the interactions involved in the formation of the ligand-RNA complex using biochemical and biophysical techniques.

Do not hesitate to follow us on twitter @MariaDuca_CNRS for the latest news!

November 2019: Maria Duca is invited speaker at ICBS2019 to be held in Hyderabad (India) in November 2019 as well as at the symposium about Targeting RNA in Franckfurt (Germany).

September 2019: Our new article is out in ChemCommun !

July 2019: New ANR-PRC grant obtained this year entitled "A new therapeutic target for ischemic-related injuries: application in organ transplantation" in collaboration with Michel TAUC at LP2M.

July 2019: Céline Martin won the best poster award at RICT2019 !

May 2019: Review about small-molecule RNA ligands accepted in MedChemComm !

April 2019: Oral communication accepted for European Chemical Biology Symposium in Madrid April 2019

January 2019: Welcome to Benjamin Zagiel (@BenjaminZagiel), we are very happy to have him in the group....new pictures coming soon....

December 2018: Céline, Chloé and Sylvain are ready to take part to Young Research Fellows Meeting in Paris next February

December 2018: our last work about inhibition of microRNA biogenesis using small molecules is out in ACS Omega and is open access!

October 2018: welcome to Sylvain Poulet who is beginning his PhD in our group thanks to UCA-JEDI IDEX fellowship!

September 2018: check out our last paper published in Org. Biomol. Chem. !!

September 2018: Maria Duca will give a talk at ISMC in Ljiubljana, check the finalized program!

July 2018: Céline Martin and Chloé Maucort present a poster to the European School of Medicinal Chemistry (ESMEC) in Urbino, Italy

June 2018: our project about interfering with oncogenic miRNAs as an innovative therapeutic approach against glioblastoma supported by "Complexity and Diversity of Living Cells" Academy 4 of IDEX-UCA JEDI

January 2018: Our paper Modulation of oncogenic miRNA biogenesis using functionalized polyamines just published in Scientific Reports (Ed. Nature).

Publications


2019

  • Joly, J.P., Gaysinski, M., Zara, L., Duca, M., Benhida, R. Functionalized C-nucleosides as remarkable RNA binders: targeting of prokaryotic ribosomal A-site RNA. Chem. Commun. 2019 55, 10432.
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2018

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  • Vo, D.D., Becquart, C., Tran, T.P.A., Di Giorgio, A., Darfeuille, F., Staedel, C., Duca, M. Building of neomycin-nucleobase-aminoacid conjugates for the inhibition of oncogenic microRNAs biogenesis Org. Biomol. Chem. 2018 16, 6262.
  • 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 8, 1667.

2017

  • Vo, D.D., Duca, M. Design of multimodal small molecules targeting miRNAs biogenesis : synthesis and in vitro evaluation Methods Mol. Biol.2017 1517, 137.
  • Duca, M. Interfering with Enzymatic steps of microRNAs pathway using small molecules in Advances in Studies on Enzyme Inhibitors as Drugs Ed. Novascience 2017 vol.1, p.83.

2016

  • D.D. Vo, T.P.A. Tran, C. Staedel, R. Benhida, A. Di Giorgio, M. Duca (2016) Oncogenic microRNAs biogenesis as a drug target : structure-activity relationship studies on novel aminoglycoside conjugates Chem. Eur. J. 22, 5350-5362.
  • A. Di Giorgio, T. P. A. Tran, M. Duca (2016) Small-molecule approaches toward the targeting of oncogenic microRNAs : roadmap for the discovery of RNA modulators, Future Medicinal Chemistry, 8, 803-816.

2015

  • T.P.A. Tran, D.D. Vo, A. Di Giorgio, M. Duca (2015) Ribosome-targeting antibiotics as inhibitors of oncogenic microRNAs biogenesis : Old scaffolds for new perspectives in RNA targeting. Bioorg. Med. Chem. 23, 5334-5344
  • L. Pascale, A. López González, A. Di Giorgio, M. Gaysinski, J. Teixido Closa, R. Estrada Tejedor, S. Azoulay, N. Patino (2015) Deciphering structure-activity relationships in a series of Tat/TAR inhibitors. J. Biomol. Struct. Dyn.

2014

  • D.D. Vo, C. Staedel, L. Zehnacker, R. Benhida, F. Darfeuille, M. Duca (2014) Targeting the production of oncogenic microRNAs with multimodal synthetic small molecules. ACS Chem. Biol., 9, 711-21.
  • J.P. Joly, G. Mata, P. Eldin, L. Briant, F. Fontaine-Vive, M. Duca, R. Benhida (2014). Artificial nucleobase-amino acid conjugates : a new class of TAR RNA binding agents. Chem Eur J, 20, 2071-9
  • Rocchi S., Ballotti R., Benhida R., Cerezo M., Duca M., Joly, J.P. Preparation of arylsulfonamido thiazole derivs. as antitumor agents PCT Int. Appl. (2014), WO 2014072486

2013

  • L. Pascale, S. Azoulay, A. Di Giorgio, L. Zenacker, M. Gaysinski, P. Clayette, N. Patino (2013). Thermodynamic studies of a series of homologous HIV-1 TAR RNA ligands reveal that loose binders are stronger Tat competitors than tight ones. Nucleic Acids Res 11, 5851-63 (IF 8.28).
  • C.Y. Darini, P. Martin, S. Azoulay, M.D. Drici, P. Hofman, S. Obba, C. Dani, A. Ladoux (2013). Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential. Cell Death Dis 4, E706

2012

  • P. Vekhoff, M. Duca, D. Guianvarc’h, R. Benhida, P.B. Arimondo (2012). Sequence specific base pair mimics are efficient topoisomerase IB inhibitors. Biochemistry, 51, 43-51.
  • G. Upert, A. Di Giorgio, A. Upadhyay, D. Manvar, N. Pandey, V.N. Pandey, N. Patino (2012). Inhibition of HIV Replication by Cyclic and Hairpin PNAs Targeting the HIV-1 TAR RNA Loop. J Nucleic Acids
  • V. Malnuit, M. Duca, R. Benhida (2011). Targeting DNA base pair mismatch with artificial nucleobases. Advances and perspectives in triple helix strategy. Org. Biomol. Chem., 9, 326-36.

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.

 

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. 

 

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)

Members

Group Leader

Maria Duca 

Permanent members 

Stéphane Azoulay (Assistant Professor) 
Audrey Di Giorgio (Assistant Professor) 
Nadia Patino (Full Professor) 

Post-doctoral fellows 

Benjamin ZAGIEL (2019-2020, INCa)

PhD Students

Chloé MAUCORT (2017-2020, Institut de Recherche Servier)
Sylvain POULET (2018-2021, IDEX UCA)

Céline MARTIN (2018-2021, ANR)

Master Students

Samy AOUAD (2019, IDEX UCA)

Marc PANOSETTI (2019)

Technical Staff

Anaïs PAVEYRANNE (2018-2019, CNRS)

Former post-doctoral fellows and students

Serena DE PICCOLI (M2, 2017). Current position: PhD at ISIS (Strasbourg) 
Thi Phuong Anh TRAN, PhD (2013-2016). Current position: Lecturer at University of Nha Trang (Vietnam)
Dr. Duc Duy VO, Post-doc (2012-2014). Current position: Research Scientist at Uppsala University (Sweden) 
Jean-Patrick JOLY, PhD (2009-2013). Post-doc at Institut de Chimie Radicalaire of the University of Marseille 
Oleg Borodin, M2 (2016). Current position: PhD student in FAU Erlangen-Nuremberg (Germany)
Coralie CHARRAT, M2 (2012). 
Guillaume MATA, M2 (2012). Current position : after a PhD at ETH (Zurich), SNF Researcher at Stanford University.
Lorena ZARA, M2 (2013). Current position : PhD at Laboratoire ARNA (Bordeaux)

Anita RAYAR (post-doc 2017-2018) 
Klara ARADI (post-doc 2018)
Alexandra Gresika (2016-2018).


Why Nice

Université Côte d’Azur among the 10 main French universities 

The Université Côte d’Azur (UCA) is a community of universities and institutions (COMUE) which, in addition to its 13 members, groups together public and private entities of higher education and research. In 2016, UCA was awarded the very selective "IDEX" Future Investment Program with the UCAJedi (Joint, Excellent & Dynamic Initiative) project aimed at identifying the top 10 French universities. The investment of nearly 600 million euros that will be allocated to UCA will generate 14.5 million euros per year.

The Institute of Chemistry of Nice belongs to Université Côte d’Azur and includes four main research axes :

  • Bioactive Molecules
  • Fragrances : synthesis and molecular modeling
  • Human and Environmental Radiochemistry
  • Sustainable materials and polymers

TNA research group belongs to the Bioactive Molecules axes. 



Living in Nice 

Capital of the French Riviera, Nice enables quick and easy access to the entire coastline as well as the mountain resorts and the Mercantour National Park, only 1.5 hours from the sea. In this natural environment, every season is conducive to incentives, unusual itineraries, and adventures. Nice enjoys an exceptional microclimate which contributes to its eminence, with more than 300 days of sunny days.

Located in the heart of the city, just 15 minutes from the Airport (2ⁿd International airport in France), Sciences Campus includes chemistry, biology and physics institutes together with mathematics, informatics and geology.


Positions available

PhD Fellowships

French Minister funding opportunities are available for PhD students (application deadline in March 2019). Candidates should forward a CV and contact information to maria.duca@univ-cotedazur.fr.

Master’s Projects 

Highly motivated candidates should send their CV and a transcript of their marks to maria.duca@unice.fr. Candidates should contact me in fall-winter 2019 for a project starting in early 2020.