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Lopez Marie

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Research themes

- Design, synthesis and characterisation of small-molecule enzyme inhibitors for anticancer or anti-infectious therapies
- Targeting of epigenetic mechanisms and especially DNA methylation in cancer
- Application of chemical-biology strategies to better understand epigenetic mechanisms

Current research

My current research project aims at a better understanding of epigenetic mechanism and especially DNA methylation in cancer. DNA methylation in aberrant in cancer and whereas bodies of gens are hypomethylated, a hypermethylation of the tumour suppressor gene promoter regions is observed. This methylation pattern is associated with tumour suppressor gene silencing and induces tumour formation and maintenance. DNA methyltransferases (DNMTs) are the enzyme catalysing DNA methylation. As a highly important mechanism of cancer DNA methylation targeting is increasingly studied and two nucleoside analogues, inhibitors of DNMTs, are currently used as anticancer treatments. Nevertheless, the instability of those molecules and their associated side effects spark the interest to improve DNA methylation targeting in cancer.
To this end, my first research project is to discover new small molecules inhibiting DNMTs by improving existing inhibitors, synthesising multivalent systems of DNMT inhibitors or designing and synthesising hydride epigenetic modulator molecules.
The second research interest is to develop chemical-biology methods to increase our understanding of epigenetic mechanisms in cancer. Thus, we design and synthesis chemical tools, called chemical probes, capable of trapping DNMT partners directly in living cells using bio-orthogonal chemistry. Our goal is to identify DNMT partners belonging to the same enzymatic complex as DNMT that are specific to cancer cells and which can be responsible for the addressing of DNMT in the TSG promoter regions. These specific DNMT partners could then be consider as new “epitargets” to develop anticancer therapies to indirectly inhibit DNA methylation with less side effect than existing active compounds.

Research Profile

I get my PhD in 2007 Chemistry-Biology at the University of Grenoble. During this project, I synthesised functionalised monosaccharides and used chemoenzymatic synthesis to prepare xylogluco-oligosaccharides and study their interactions with cellulose, using isothermal titration calorimetry (ITC), adsorption isotherm determination and solid NMR. The aim was to mimic the xyloglucan-cellulose network of plant cell walls and identify the key parameters for these interactions.
I was then recruited in 2008 for a post-doctoral fellowship at Eskitis Institut in Brisbane (Australia) on an Australian Research Council (ARC) fellowship to work on the design and synthesis of glycosulfonamides as carbonic anhydrase inhibitors as anticancer therapies.
I moved then to Montpellier in 2011 to carry out a project at the interface of chemistry and biology where I purified Mycobacterium tuberculosis histidinol dehydrogenase (HDH), a virulence factor, of this pathogen and synthesised HDH inhibitors to be used as anti-infectious compounds.
In 2013, I was recruited as CNRS research associate and started my project about epigenetics and cancer at the ETaC laboratory. The aim of my research project is to improve DNA methylation targeting in cancer. To do so, I synthesis new DNA methyltransferase (DNMT) inhibitors and develop chemical-biology strategies to better understand what are the actors involved in the aberrant DNA methylation pattern in cancer cells.

List of publications

1. M. Lopez, L. Halby, P. B. Arimondo (in press) “DNMT inhibitors”
2. M. Lopez, M. Leroy, C. Etievant, F. Ausseil, A. Gagnon, P. B. Arimondo 2016 "Drug Discovery Methods". In G. Egger & P. Arimondo (Eds), Drug Discovery in Cancer Epigenetics, Elsevier.
3. D. Pechalrieu, M. Lopez Compounds for use in the treatment of mycobacterial infections : a patent evaluation (WO2014049107A1), Expert Opinion on Therapeutic Patents 2015, 25(6), 729-735
4. F. Turtaut, M. Lopez, S. Ouahrani-Bettache, S. Köhler, J.-Y. Winum Oxo- and thiooxo-imidazo[1,5-c]pyrimidine molecule library : beyond their interest in inhibition of Brucella suis histidinol dehydrogenase, a powerful protection tool in the synthesis of histidine analogues, Bioorganic and Medicinal Chemistry Letters 2014, 24, 5008-5010
5. M. Lopez, L. F. Bornaghi, S.-A. Poulsen Synthesis of sulfomanide-conjugated glycosyl-amino acid building blocks, Carbohydrate research 2014, 386, 78-85
6. K. D’ambrosio, M. Lopez, N. A Dathan, S. Ouahrani-Bettache, S. Köhler, G. Ascione, S. Maria Monti, J.-Y.Winum, G. De Simone Structural basis for the rational design of new anti-Brucella agents : the crystal structure of the C366S mutant of HDH from Brucella suis, Biochimie 2014, 97, 114-120
7. K. T. Andrews, G. M. Fisher, S. D.M. Sumanadasa, T. Skinner-Adams, J. Moeker, M. Lopez and S.-A. Poulsen Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment, Bioorganic and Medicinal Chemistry Letters 2013, 23(22), 6114-6117
8. C. J. Carroux, J. Moeker, J. Motte, M. Lopez, L. F. Bornaghi, K. Katneni, E. Ryan, J. Morizzi, D. M. Shackleford, S. A. Charman, S.-A. Poulsen Synthesis of acylated glycoconjugates as templates to investigate in vitro biopharmaceutical properties, Bioorganic and Medicinal Chemistry Letters 2013, 23 (2), 455-459
9. M. Lopez, S. Köhler, J.-Y. Winum Zinc metalloenzymes as new targets against the bacterial pathogen Brucella, Journal of Inorganic Biochemistry 2012, 111, 138-145
10. J. Möker, K. Teruya, S. Rossit, B. L. Wilkinson, M. Lopez, L. F. Bornaghi, A. Innocenti, C. T. Supuran, S.-A. Poulsen Design and synthesis of thiourea inhibitors targeting transmembrane carbonic anhydrases, Bioorganic and Medicinal Chemistry 2012, 20 (7), 2392-2404
11. M. Lopez, S. Fort, H. Bizot, A. Buléon, H. Driguez Chemo-enzymatic Synthesis of Xylogluco-Oligosaccharides and their Interactions with Cellulose, Carbohydrate polymers 2012, 88, 185-193
12. M. Lopez, H. Vu, C. K.-L. Wang, M. G. Wolf, G. Groenhof, A. Innocenti , C. T. Supuran, S.-A. Poulsen Promiscuity of Carbonic Anhydrase II. Unexpected Ester Hydrolysis of Carbohydrate-Based Sulfamate Inhibitors, Journal of the American Chemical Society 2011, 133, 18452-18462
13. J. C. Morris, J. Chiche, C. Grellier, M. Lopez, L. F. Bornaghi, A. Maresca, C. T. Supuran, J. Pouysségur, S.-A. Poulsen Targeting Hypoxic Tumor Cell Viability with Carbohydrate-Based Carbonic Anhydrase IX and XII Inhibitors, Journal of Medicinal Chemistry 2011, 54, 6905-6918
14. M. Lopez, L. F. Bornaghi, H. Driguez, S.-A. Poulsen Synthesis of sulfonamide-bridged glycomimetics, Journal of Organic Chemistry 2011, 76 (9), 2965-2975 (featured article)
15. M. Lopez, J. Trajkovic, L. F. Bornaghi, A. Innocenti, D. Vullo, C. T. Supuran, S.-A. Poulsen Design, Synthesis, and Biological Evaluation of Novel Carbohydrate-Based Sulfamates as Carbonic Anhydrase Inhibitors, Journal of Medicinal Chemistry 2011, 54 (5), 1481-1489
16. M. Lopez, A. J. Salmon, C. T. Supuran, S.-A. Poulsen Carbonic Anhydrase Inhibitors Developed Through ‘Click Tailing’ Current Pharmaceutical Design 2010, 16, 3277-3287
17. M. Lopez, H. Bizot, G. Chambat, M.-F. Marais, A. Zykwinska, M.-C. Ralet, H. Driguez, A. Buléon Enthalpic Studies of Xyloglucan-Cellulose Interactions Biomacromolecules 2010, 11, 1417-1428
18. B. L. Wilkinson, L.F. Bornaghi, M. Lopez, P. Healy, S.-A. Poulsen, Todd Houston Synthesis of N-Propargyl Iminosugar Scaffolds for Compound Library Generation using Click Chemistry Australian Journal of Chemistry 2010, 63, 821-829
19. M. Lopez, L. F. Bornaghi, A. Innocenti, D. Vullo, S. A. Charman, C. T. Supuran, S.-A. Poulsen Sulfonamide Linked Neoglycoconjugates−A New Class of Inhibitors for Cancer-Associated Carbonic Anhydrases Journal of Medicinal Chemistry 2010, 53 (7), 2913–2926
20. M. Lopez, B. Paul, A. Hofmann, J. Morizzi, Quoc K. Wu, S. A. Charman, A. Innocenti, D. Vullo, C. T. Supuran, S.-A. Poulsen S-Glycosyl Primary Sulfonamides − A New Structural Class for Selective Inhibition of Cancer-Associated Carbonic Anhydrases Journal of Medicinal Chemistry 2009, 52, 6421-6432
21. M. Lopez, N. Drillaud, L. F. Bornaghi, S.-A. Poulsen Synthesis of S-Glycosyl Primary Sulfonamides Journal of Organic Chemistry 2009, 74 (7), 2811-2816
22. M. Singer, M. Lopez, L. F. Bornaghi, A. Innocenti, D. Vullo, C. T. Supuran, S.-A. Poulsen Inhibition of carbonic anhydrase isozymes with benzene sulfonamides incorporating thio, sulfinyl and sulfonyl glycoside moieties Bioorganic & Medicinal Chemistry Letters 2009, 19(8), 2273-2276
23. K. Piens, A.-M. Henriksson, F. Gullfot, M. Lopez, R. Fauré, F. M. Ibatullin, T. T. Teeri, H. Driguez, H. Brumer Glycosynthase activity of hybrid aspen xyloglucan endo-transglycosylase PttXET16-34 nucleophile mutants Organic & Biomolecular Chemistry 2007, 5(24), 3971-3978