Research topics of the team
ANALYTICAL AND CELLULAR CHEMISTRY-TOXICOLOGY (Olivier Laprévote)
The “Analytical Chemistry and Cell Toxicology” team was built by successive associations of personalities with specific know-how, at the best level in their respective fields, with the aim of allowing the emergence of original works at the interfaces of the different disciplines represented (Biology, Cell Toxicology, Analytical Chemistry, Organic Chemistry, Phytochemistry, Computerized Chemistry and Modelling). The two main tools hosted by that the team are the mass spectrometry and cell culture platforms, promoting initially the characterisation of toxicity markers on the cell models developed in the laboratory. The analytical methods then evolved logically towards metabolomics and more precisely towards lipidomic approaches, the lipid metabolism being particularly sensitive to alterations due to toxic exposures. The integration of the new approaches for spectral modelling and molecular networking developed by Grégory Genta-Jouve as part of his research activity in Phytochemistry proved to be extraordinarily valuable for the characterization of lipidomes. At the same time, the modelling of chemical reactions by the Density Functional Theory (DFT) and of spectral data gave a new momentum to the organic synthesis activity of the team, endorsed by Emmanuel Roulland. The latter’s chemist skills are used to decipher structural patterns specific to some molecular structures, as demonstrated by our most recent results on the characterization of positions and stereochemistry of unsaturations on lipid structures. The structuring of the topics which are presented below therefore remains artificial and only imperfectly describes the network of interactions that underlie them.
ANALYTICAL TOXICOLOGY – MASS SPECTROMETRY – LIPIDOMICS (Nicolas Auzeil)
The team’s research in mass spectrometry focuses on the study of lipidomes in various contexts, including (i) the impact of endocrine disruptors on human neurodevelopment and their potential role in the occurrence of certain neuro-behavioral disorders and (ii) the mechanisms involved in the occurrence of eye dryness, particularly when linked to the use of cationic preservatives in eye drops.[1]
Ultimately, in both cases, the objective is the search for lipid biomarkers of exposures to environmental toxicants that can help in the diagnosis and/or prognostication of pathologies. This activity is based on the use of cellular models (cell lines of oligodendrocytes and cornea), animals (rodents) and samples taken from humans.
Lipidomic analyses are carried out by ultra-performance liquid chromatography coupled with high-resolution mass spectrometry, which allow the use of molecular networks after a pre-processing step of the raw data. This new and innovative approach (pioneer in the case of lipidomics) [2] provides very accurate information on the structure of lipids which are disturbed by exposure to a toxic or by pathological conditions. The use of single- and multivariate statistical analyses is also necessary.
The methods developed in the team are the result of close collaborations between the team’s analysts, around Nicolas Auzeil, and Grégory Genta-Jouve for the modelling and computational aspects, and Emmanuel Roulland for structurally specific chemical derivatives.
- R. Magny, K. Kessal, A. Regazzetti, A. Ben Yedder, C. Baudouin, S. Mélik Parsadaniantz, F. Brignole-Baudouin, O. Laprévote, N. Auzeil. BBA, Mol Cell Biol. Lp 2020, 1865(9), Article Number 158728 (2020)
- R. Magny, A. Regazzetti, K. Kessal, G. Genta-Jouve, C. Baudouin, S. Mélik Parsadaniantz, F. Brignole-Baudouin, O. Laprévote, N. Auzeil. Metabolites 2020 10(6), Article Number 225
TOTAL SYNTHESIS (Emmanuel Roulland)
Total synthesis of Tiacumicine B
Bacteria’s resistance to antibiotics is a major biomedical risk that is increasing dangerously. The discovery and exploitation of new molecules capable of counteracting these resistances is therefore a priority objective. Tiacumicin B (or fidaxomicin, Scheme 1) is a naturally occurring macrolide with unique antibiotic properties due to its action on the switch-region of bacterial RNA polymerase.
The program we are developing has led to the development of a total synthesis of tiacumicin B [1] which opens a reliable pathway to analogues of this molecule of interest. This total synthesis was made possible by innovations in the synthesis strategy involving new synthesis methods (Scheme 1) and the use of DFT computation.[1] The ANR agency supported this ambitious project led by Emmanuel Roulland in collaboration with the team of Jean-Marie Beau and Stephanie Norsikian of the ICSN-CNRS in Gif-sur-Yvette.
- a) S. Norsikian, C. Tresse, M. François-Eude, L. Jeanne-Julien, G. Masson, V. Servajean, G. Genta-Jouve, J.-M. Beau,E. Roulland, Angew. Chem. Int. Ed., 2020, 59, 6612 – 6616. b) L. Jeanne-Julien, G. Masson, E. Astier, G. Genta-Jouve,V. Servajean, J.-M. Beau, S. Norsikian, E. Roulland, J. Org. Chem.2018, 83, 921 – 929. c) L. Jeanne-Julien, G. Masson, E. Astier, G. Genta-Jouve,V. Servajean, J.-M. Beau, S. Norsikian, E. Roulland, Org. Lett.2017, 19, 4006 – 4009. d) E. Roulland, Synthesis 2018, 50,4189 – 4200.
Structural Determination of a New Marine Natural Substance by Calculation and Confirmation by Total Synthesis
With an allene function in the middle of its chain and therefore with an axial chirality, the structure of the puna’auic acid (Scheme 2) is a exception in natural substances. Simulations of NMR and circular dichroism spectra based on DFT calculations performed by Grégory Genta-Jouve led to the choice of an enantiomer for puna’auic acid, this prediction being confirmed by total synthesis.[1]
The success of this approach underlines the relevance of DFT modeling of organic reactions and spectral data (Gregory Genta-Jouve) and coupled with total synthesis (Emmanuel Roulland).
- a) L. Jeanne-Julien, G. Masson, R. Kouoi, A. Regazzetti, G. Genta-Jouve, V. Gandon, E. Roulland, Org. Lett. 2019, 21, 3136 – 3141. b) L. Jeanne-Julien, E. Astier, R. Lai-Kuen, G. Genta-Jouve, E. Roulland, Org. Lett. 2018, 20, 1430 – 1434. c) E. Roulland, H. Solanki, K. Calabro, M. Zubia, G. Genta-Jouve, O. Thomas, Org. Lett 2018, 20, 2311 – 2314
Anticipating marine and terrestrial natural products (Grégory Genta-Jouve).
In this axis, we are interested in the identification of original natural substances using numerical methods such as in silico metabolization and prediction of mass spectrometry fragmentation spectra. All these tools are brought together on a platform put online and accessible for free (https://metwork.pharmacie.parisdescartes.fr/). In contrast to the “classic” approach in phytochemistry that results from the initial analysis of extracts and the individual structural identification of their components, our approach allows us to anticipate the structures present in a given extract and confirm them at high speed by comparing the experimental data obtained by mass spectrometry with those resulting from the modeling of the spectra.[1]
- a) C. Audoin, V. Cocandeau, O. P. Thomas, A. Bruschini, S. Holderith, G. Genta-Jouve, Metabolites 2014, 4(2), 421-432. b) A. E. Fox Ramos, C. Pavesi, M. Litaudon, V. Dumontet, E. Poupon, P. Champy, G. Genta-Jouve*, M. A. Beniddir* Anal. Chem. 2019, 91(17), 11247–11252
CELLULAR TOXICOLOGY – ALTERNATIVE METHODS TO ANIMAL EXPERIMENTATION b (PATRICE RAT – ELODIE OLIVIER)
The Cellular Toxicology team has made it a specialty and a goal to develop alternative methods to animal experiments in the field of toxicology. We first highlighted the key role of the P2X7 receptor in ocular toxicity processes, whether induced by an external factor, such as multifunctional solutions for cleaning contact lenses, or by a degenerative process linked to a pathology such as age-related macular degeneration. We then studied the role of this P2X7 receptor in skin degeneration induced by photoaging. More recently, we have studied the role of this receptor in placental toxicology and more particularly its activation by molecules with endocrine disrupting properties. This work has allowed us to propose a human placental model applicable to chemical molecules but also to plant extracts such as oils for the evaluation of placental toxicology.
Publications :
- Fouyet S., et al. Bisphenol A, Bisphenol F, Bisphenol S: The bad and the ugly. Where is the good? Life 2021
- Olivier E et al. JEG-3 placental cells in toxicology studies: a promising tool to reveal pregnancy disorders. Anat Cell Biol 2021
- Dutot M et al. The role of P2X7 receptor in ocular stresses: a potential therapeutic target. Vision 2017
