Structure and Photoactivatable Probes for Nucleic Acids and Kinases

Marie-Paule Teulade-Fichou

Marie-Paule Teulade-Fichou Team Leader Tel:

Our group works on the design of compounds targeting non-B nucleic acid structures and certain kinases involved in cancer. The group has a broad expertise in bio-organic chemistry and optical spectroscopy with a strong background in supramolecular chemistry and molecular recognition. Our final aims are to open new perspectives in the discovery of anticancer drugs and mechanistic tools.

Context : Our current interest is focused on the design of new nucleic acid targeted compounds for anticancer research and for elucidating DNA-related molecular basis of cancer.
It is well recognized that DNA sequences containing repeats of heterocyclic bases are highly susceptible to aberrant replication and perturbation of other DNA-related processes such as recombination and transcription. These dysfunctions may lead ultimately to modifications of the genetic material) and may have a role in explaining mechanisms linked to cancer development or more largely be involved in pathogenic rearrangements genome-wide. Repeat-containing DNA domains are highly prone to form non-canonical secondary structures due to self-assembly of bases via various H-bonding modes (mismatched pairs, base-triplets or quartets). The generated structures (mismatched sites, hairpins, triplex, quadruplex) are known (for some) or suspected (for others) to be involved in genetic instability and in pathogenic dysfunctions.
Our team is interested in the recognition of these non-canonical structures locally formed in DNA by means of specifically designed small molecules (i.e. ligands) that will bind the target structure with high specificity. The primary objectives of this research are two-folded, firstly to provide structure probes usable in various in vitro and cellular models for exploring the polymorphism of DNA; secondly to provide functional probes reporting or acting on the target structure (fluorescent signalling, covalent crosslinking). Of note the design and synthesis of targeted fluorescent molecules compatible with cellular imaging represents a subtopic of our research tightly intertwined with the structure-targeting topic. The final objectives of this research are to create new chemical biology tools for studying and controlling the formation of the target structures as well as their processing by proteins. Ultimately we aim at the discovery of better targeted (regiospecific) DNA interactive agents that may become clinical drugs for anticancer chemotherapy.
Our specific approaches towards the identification of active scaffolds are based on rational design (shape complementarity- topology adaptation) and on screening methods. Thus we developed home-made assays amenable to high-throughput screening. These are combined with the use of state of the art optical spectroscopy (UV-Vis, fluorescence, circular dichroïsm) and biochemical methods (gel electrophoresis, pull down assay) for quantitative evaluation of NA-ligands interactions. We also intend to a deep understanding of non-covalent interactions at the atomic level by means of molecular modelling analyses.

 

 

Key publications

Year of publication 2019

Franck Court, Elisa Le Boiteux, Anne Fogli, Mélanie Müller-Barthélémy, Catherine Vaurs-Barrière, Emmanuel Chautard, Bruno Pereira, Julian Biau, Jean-Louis Kemeny, Toufic Khalil, Lucie Karayan-Tapon, Pierre Verrelle, Philippe Arnaud (2019 Sep 20)

Transcriptional alterations in glioma result primarily from DNA methylation-independent mechanisms.

Genome research : Epub ahead of print : DOI : 10.1101/gr.249219.119
Angrand G., Quillévéré A., Loaëc N., Daskalogianni C., Granzhan A., Teulade-Fichou M.P., Fahraeus R., Prado Martins R., Blondel M. (2019 Sep 1)

Sneaking Out for Happy Hour: Yeast-Based Approaches to Explore and Modulate Immune Response and Immune Evasion

Genes : 10 : 667-689 : DOI : 10.3390/genes10090667
Abegão L.M.G., Fonseca R.D., Santos F.A., Rodrigues J.J., Kamada K., Mendonça C.R., Piguel S., De Boni L. (2019 Aug 23)

First molecular electronic hyperpolarizability of series of π-conjugated oxazole dyes in solution: an experimental and theoretical study

RSC Adv. : 9 : 26476-26482 : DOI : 10.1039/C9RA05246A
Xiao Xie, Michela Zuffo, Marie-Paule Teulade-Fichou, Anton Granzhan (2019 Aug 6)

Identification of optimal fluorescent probes for G-quadruplex nucleic acids through systematic exploration of mono- and distyryl dye libraries

Beilstein Journal of Organic Chemistry : 15 : 1872–1889 : DOI : 10.3762/bjoc.15.183
Birzu C., Hillairet A., Giry M., Grandin N., Verrelle P., Mokhtari K., Marie Y., Hoang-Xuan K., Delattre J., Idbaih A., Charbonneau M., Sanson M., Alentorn A. (2019 Aug 1)

OS9.7 Telomere length, TERTp mutation and ALT status in adult diffuse gliomas

Neuro-Oncology : 21 : iii19-iii20 : DOI : 10.1093/neuonc/noz126.065
Paulina Prorok, Marie Artufel, Antoine Aze, Philippe Coulombe, Isabelle Peiffer, Laurent Lacroix, Aurore Guédin, Jean-Louis Mergny, Julia Damaschke, Aloys Schepers, Benoit Ballester, Marcel Méchali (2019 Jul 24)

Involvement of G-quadruplex regions in mammalian replication origin activity.

Nature communications : 3274 : DOI : 10.1038/s41467-019-11104-0
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