Molecular approaches for new antimalarial strategies

Our research is devoted to the analysis of molecular, biochemical and cellular processes of the human malaria parasite, Plasmodium falciparum with the aim to identify essential steps that we can then exploit for the development of new future antimalarial drugs. Our domains of interest are the Plasmodium phospholipid metabolism and the molecular landscape of DNA replication.

Our group has greatly contributed to the elucidation of the PL metabolic pathways present in the malaria parasite and has exploited this knowledge for the development of antimalarial compounds that target the parasite PL metabolism (development of a choline analogue (T3/albitiazolium) up to Clinical Phase II in collaboration with Sanofi). The objective of our current research is to deepen our understanding of the biology of lipids in the malaria parasite, and thereby identify essential components of this metabolism.

The aim of our fundamental research is the discovery of essential processes that we can then exploit for the development of new and potent antimalarial drugs. Our group is continuously active in antimalarial drug testing and drug development given our long standing expertise in this field.

Responsable

Rachel CERDAN
Professeur (PR) UM
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· 2-year postdoctoral position in Molecular and Cellular Biology of Malaria (pdf)

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Theme 1: Deciphering the Plasmodium phospholipid metabolism and development of antimalarial molecules by structure-based rational drug design

Phospholipids (PLs) are essential components of biological membranes. The malaria parasite Plasmodium falciparum, uses its own metabolic machinery to synthetized PLs through a complex network of metabolic pathways. The most abundant PLs in the P. falciparum infected red blood cell are phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) and they constitute the bulk of the lipids that form parasite membranes.

Based on lipidomics we recently obtained a comprehensive overview of the metabolism of the main PLs in P. falciparum. Our data raised new questions about the sources of PLs, the links between the multiple pathways and the existence of some specific enzymatic steps.

Our objective is to identify the bottlenecks, the compensatory effects and the interplay between the different PL pathways by lipidomic studies using deuterium-labelled precursors. The findings will allow us to select new therapeutic targets.

We previously identified the enzyme CCT (CTP:phosphocholine cytidylyltransferase) in the PC biosynthesis pathway as promising potential target. Our team determined the 3D structures of the PfCCT catalytic domain in the absence and in the presence of its substrates and its product.

Our objective is to identify and to optimize new PfCCT specific inhibitors with antimalarial activity using an integrated target-based approach combining screening of ligands and 3D structure determination.

Phosphoinositides (PPIs), the phosphorylated derivatives of PI, are quantitatively minor PLs with important functions in intracellular signalling and membrane identity. We identified the PPIs present in P. falciparum-infected erythrocytes and produced a catalogue of enzymes and binding proteins that are predicted in the Plasmodium proteome.

Our objective is to characterise lipid kinases, lipid phosphatases and PPI-binding proteins and to evaluate their potential as future drug targets.

Theme 2: The genetic landscape of DNA replication in P. falciparum
Theme 3: Development of new compounds and evaluation of their antimalarial potential
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