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PhD position proposed in parasitology, phytochemistry & drug discovery

Titre du projet :

 Développement de médicaments antipaludiques à partir des plantes Artemisia : une approche innovante de purification bio-guidée de composés "hits" ciblant des stades parasitaires réfractaires.

Main PI for the project:

Dr. Romain DUVAL (thesis director)

UMR IRD 261 MERIT

Faculty of Pharmacy of Paris - University of Paris

4 Avenue de l'Observatoire, 75006 Paris - France

romain.duval@ird.fr

Co-PIs for the project:

Prof. Steffen BORRMANN (thesis co-director)

Institute for Tropical Medicine

University of Tübingen, Tübingen - GERMANY

steffen.borrmann@uni-tuebingen.de

Prof. Emeritus Dominique MAZIER

CIMI - Sorbonne Université

75014 Paris - FRANCE

dominique.mazier@sorbonne-universite.fr

Keywords: Malaria, Artemisia annua, Artemisia afra, Plasmodium, P. falciparum, P. vivax, P. cynomolgii, hepatic stages, gametocytes

Abstract:

We are looking for a PhD candidate to identify then investigate novel antiplasmodial molecules contained in Artemisia annua (from which the potent antimalarial compound artemisinin is extracted) and Artemisia afra (devoid of artemisinin). A. annua has been used historically to treat malaria fever in China but remains in use as an alternative treatment in malaria endemic areas with limited access to standard, WHO recommended, first-line artemisinin-based combination therapies. A. afra is also being increasingly utilized in malaria-plagued countries of Africa. Using traditional preparations, our group already demonstrated that (i) Artemisia plant infusions were highly active against the hepatic stages of various Plasmodium species, including the most fatal P. falciparum and the relapse-causing P. vivax and P. cynomolgi and that (ii) these activities were essentially artemisinin-independent.[1] Strong inhibitory effects of the infusions were previously shown against P. falciparum gametocytes,[2] responsible for the parasite transmission from the human host to the Anopheles mosquito vector. These stages are notoriously drug-insensitive except from atovaquone (P. falciparum hepatic stages) and primaquine/tafenoquine (P. falciparum, P. vivax and P. cynomolgi hepatic stages & P. falciparum gametocytes), the latter being limited by the risk of haemolysis in G6PD-deficient patients and dependence on the host metabolism for effectiveness.

We have devised an innovative dereplicative fractioning strategy, under the form of a bio-guided approach, aiming to circumvent the inherent cost, labor intensiveness and duration of classical phytochemical purifications. The objectives of this approach are in a first step to rapidly identify and purify "hit" compounds present in the Artemisia plants, and responsible for their peculiar inhibitory effects. In a second step, pure active compounds will be used to study their mechanism of action against malaria parasites using established bioassays. These investigations will be made in conjunction with chemo-biological approaches such as "hit" chemical labeling, en route to protein target identification by means of cell imaging and proteomic methodologies.[3] Eventually, these targets will be validated using biochemical (e. g., enzymatic) and/or molecular biology (e. g., generation of mutant KO parasites) methods.

This project should help at identifying novel natural "hit" compounds active against specific stages of Plasmodium parasites, together with novel modes of actions and targets. It will benefit from the complementary expertise of Dr. Romain DUVAL (phytochemistry & chemical biology), Prof. Dominique MAZIER (biology of Plasmodium hepatic stages) and Prof. Steffen BORRMANN (translational parasitology).

Requirements:

The candidate:

-          should have an M.Sc. in biological sciences with a GPA grade of 3 out of 4

-          should be able to converse in English and/or French

-          should be able to demonstrate a strong interest in the field of parasitology and antimalarial drug discovery, with emphasis on natural products

The PhD candidate would be enrolled in Paris, France, for a period of three–four years. The PhD is funded by a stipend of the Tübingen University with additional funding for health insurance and a research-related travel allowance.

For further information and application, please contact Dr. Romain DUVAL, Prof. Steffen BORRMANN or Prof. Dominique MAZIER.

[1] Artemisinin-independent inhibitory activity of Artemisia sp. infusions against different Plasmodium stages including relapse-causing hypnozoites. K. Ashraf, S. Tajeri, C-S. Arnold, N. Amanzougaghene, J-F. Franetich, A. Vantaux, V. Soulard, M. Bordessoulles, G. Cazals, T. Bousema, G-J. van Gemert, R. Le Grand, N. Dereuddre-Bosquet, J-C. Barale, B. Witkowski, G. Snounou, R. Duval,* C. Y. Botté* and D. Mazier,* Life Sci. All. 2021, 5, 3, e202101237.

[2] In vitro reduction of Plasmodium falciparum gametocytes: Artemisia spp. tea infusions vs. artemisinin. D. Snider and P. J. Weathers, J. Ethnopharmacol. 2021, 268, 113638.

[3] (a) A chemically stable fluorescent mimic of dihydroartemisinin, artemether and arteether with conserved bioactivity and specificity shows high pharmacological relevance to the antimalarial drugs, A. Sissoko, P. Vásquez-Ocmín, A. Maciuk, D. Barbieri, G. Neveu, L. Rondepierre, R. Grougnet, P. Leproux, M. Blaud, K. Hammad, S. Michel, C. Lavazec, J. Clain, S. Houzé, R. Duval,* ACS Infect. Dis. 2020, 6, 1532; (b) A photoalkylative fluorogenic probe of guttiferone A for live cell imaging and proteome labeling in Plasmodium falciparum.

R. Duval.* K. Cottet, M. Blaud, A. Merckx, S. Houzé, P. Grellier, M-C. Lallemand and S. Michel, Molecules 2020, 25, 5139.