Elisabeth
DAVIOUD-CHARVET

Information

Scientific interests and projects

The spread of drug resistance in parasites jeopardises recent progress to fight malaria. Chagas’ disease and schistosomiasis are neglected tropical parasitic diseases that are considered as public health top priorities. The expertise of the research team in redox medicinal chemistry is applied to the synthesis of ‘subversive substrates’ of NAD(P)H-dependent oxidoreductases, with the aim to develop antiparasitic agents and to identify new therapeutic targets. Our interdisciplinary activity spans from the synthesis (inhibitors, redox-cyclers, metabolites, ratiometric fluorescent probes sensitive to pH and redox gradients, labelled tools for metabol- & proteo-omics) to enzymology and understanding of the mechanisms of action in living parasites. Among our recent major achievements, we showed that, depending on their chemical substitution pattern, 3-benzyl-menadione derivatives, displayed potent antiparasitic activities, both in vitro and in vivo, against Plasmodium spp., Trypanosoma cruzi, or Schistosoma mansoni worms, induced specific phenotypic effects, with no obvious sign of toxicity in mice and in G6PD-deficient red blood cells.

Our efforts are focused on the optimization of three early leads: the antimalarial plasmodione, a fast acting and transmission blocking agent, the anti-Chagas cruzidione, and the antischistosomal schistodiones. The goal of future collaborative research in ParaFrap is to optimize both early leads and synergistic partners for each disease model, to improve their pharmacokinetic properties and respective antiparasitic activities, to identify the sensitive parasite stages, their modes of action, and to validate the antiparasitic properties of the optimized compounds in vivo and with field parasite isolates. Our overarching aim is i) to select drug-candidates ready for further clinical development, ii) to unravel the modes of action through physicochemical approaches describing the interactions of antiparasitic agents with relevant targets.

Top 5 publications of the last 5 years

1. Feng L., Lanfranchi D. A., Cotos-Munoz L., Cesar Rodo E., Ehrhardt K., Goetz, A.-A., Zimmerman H., Fenaille F., Blandin S., Davioud-Charvet E. (2018) Synthesis of plasmodione metabolites and 13C-enriched plasmodione as chemical tools for drug metabolism investigation. Org. Biomol. Chem. 16, 2647 - 2665. doi: 10.1039/C8OB00227D

2. Krieg R., Jortzik E., Goetz A.-A., Blandin S., Wittlin S., Elhabiri M., Rahbari M., Nuryyeva S., Voigt K., Dahse H.-M., Brakhage A., Beckmann S., Quack T., Grevelding C. G., Pinkerton A. B., Schönecker B., Burrows J., Davioud-Charvet E.,Rahlfs S., Becker K. (2017) Arylmethylamino steroids as novel antiparasitic agents. Nat. Commun. 8:14478. Erratum : Nat Commun. 2019, 10:2997. doi:10.1038/s41467-019-11018-x

3. Ehrhardt, K., Deregnaucourt, C., Goetz, A.-A., Tzanova, T., Pradines, B., Adjalley, S. H., Blandin, S., Bagrel, D., Lanzer, M., Davioud-Charvet, E. (2016) The redox-cycler plasmodione is a fast acting antimalarial lead compound with pronounced activity against sexual and early asexual blood-stage parasites. Antimicrob. Agents Chemother. 60, 5146- 58. doi: 10.1128/AAC.02975-15

4. Cesar Rodo E., Feng L., Jida, M., Ehrhardt K., Bielitza M., Boilevin J., Lanzer M., Williams D. L., Lanfranchi, D. A., Davioud-Charvet, E. (2016) A platform of regioselective methodologies to access to polysubstituted 2-methyl-1,4-naphthoquinones derivatives: scope and limitations. Eur. J. Org. Chem. 11, 1982–1993. doi: 10.1002/ejoc.201600144

5. Bielitza, M., Belorgey, D., Ehrhardt, K., Johann, L., Lanfranchi, D. A., Gallo, V., Schwarzer, E., Mohring, F., Jortzik, E., Williams, D. L., Becker, K., Arese, P., Elhabiri, M., Davioud- Charvet E. (2015) Antimalarial NADPH-consuming redox-cyclers as superior G6PD deficiency copycats. Antioxid. Redox Signal. 22, 1337-51. 10.1089/ars.2014.6047