Drugs and Probes for Nucleic Acids Secondary Structures

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 2020

Mathieu E., Bernard A.S., Quévrain E., Zoumpoulaki M., Iriart S., Lung-Soong C., Lai B., Medjoubi K., Henry L., Nagarajan S., Poyer F., Scheitler A., Ivanovic-Burmazovic I., Marco S., somogyi a., Seksik P., Delsuc N., Policar C. (2020 May 29)

Intracellular location matters: rationalization of the anti-inflammatory activity of a manganese (II) superoxide dismutase mimic complex

Chem. Commun. : Accepted Manuscript : - : DOI : 10.1039/D0CC03398G
Stéphanie Lemaître, Florent Poyer, Paul Fréneaux, Sophie Leboucher, François Doz, Nathalie Cassoux, Carole D Thomas (2020 May 1)

Low retinal toxicity of intravitreal carboplatin associated with good retinal tumor control in transgenic murine retinoblastoma.

Clinical & experimental ophthalmology : 48 : 500-511 : DOI : 10.1111/ceo.13711
Rahima Chennoufi, Ngoc-Duong Trinh, Françoise Simon, Guillaume Bordeau, Delphine Naud-Martin, Albert Moussaron, Bertrand Cinquin, Houcine Bougherara, Béatrice Rambaud, Patrick Tauc, Céline Frochot, Marie-Paule Teulade-Fichou, Florence Mahuteau-Betzer & Eric Deprez (2020 Apr 23)

Interplay between cellular uptake, intracellular localization and the cell death mechanism in triphenylamine-mediated photoinduced cell death

Scientific Reports : 10 : 6881 : DOI : 10.1038/s41598-020-63991-9
Ehlen A., Martin C., Miron S., Julien M., Theillet F.X., Boucherit V., Ropars V., Duchambon P., El Marjou A., Zinn Justin S., Carreira A. (2020 Apr 14)

Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1

Nature Communications : 11 : 1819 : DOI : 10.1038/s41467-020-15689-9
Abhijit Saha, Patricia Duchambon, Vanessa Masson, Damarys Loew, Sophie Bombard, Marie-Paule Teulade-Fichou (2020 Mar 20)

Nucleolin Discriminates Drastically between Long-Loop and Short-Loop Quadruplexes.

Biochemistry : 59 : 1261-1272 : DOI : 10.1021/acs.biochem.9b01094
Paudel B.P., Moye A.L., Assi H.A., El-Khoury R., Cohen S.B., Birrento M.L., Samosorn S., Intharapichai K., Tomlinson C.G., Teulade-Fichou M.P., Gonz'alez C., Beck J.L., Damha M.J., van Oijen A.M., Bryan T.M. (2020 Feb 27)

A mechanism for the extension and unfolding of parallel telomeric G-quadruplexes by human telomerase at single-molecule resolution

bioRxiv : DOI : 10.1101/2020.02.26.965269
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