Sondes de structures et sondes photoactivables pour les acides nucléique et les kinases

Marie-Paule Teulade-Fichou

Marie-Paule Teulade-Fichou Chef d'équipe Tél :

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.

 

 

Publications clés

Année de publication : 2019

Nathalie Grandin, Bruno Pereira, Camille Cohen, Pauline Billard, Caroline Dehais, Catherine Carpentier, Ahmed Idbaih, Franck Bielle, François Ducray, Dominique Figarella-Branger, Jean-Yves Delattre, Marc Sanson, Patrick Lomonte, Delphine Poncet, Pierre Verrelle, Michel Charbonneau, (2019 Nov 11)

The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas.

Acta neuropathologica communications : 7 : 175 : DOI : 10.1186/s40478-019-0833-0
Priyanka Toshniwal, Michelle Nguyen, Aurore Guédin, Helena Viola, Diwei Ho, Yongeun Kim, Uditi Bhatt, Charles Bond, Livia Hool, Laurence H Hurley, Jean-Louis Mergny, Mark Fear, Fiona Wood, K Swaminathan Iyer, Nicole M Smith (2019 Nov 3)

TGF-β-induced fibrotic stress increases G-quadruplex formation in human fibroblasts.

FEBS letters : Epub ahead of print : DOI : 10.1002/1873-3468.13658
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 : 22 : 1605-1621 : 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
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