Research projects – Team 2

Theme 1: DECIPHERING THE PLASMODIUM PHOSPHOLIPID METABOLISM.

Group leader : Pr. Rachel CERDAN

PIs: Rachel Cerdan, Sharon Wein, Kai Wengelnik

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.

1- 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. OU goal 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.

2- 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: CELL CYCLE REGULATION AND CELL FATE DECISIONS IN MALARIA PARASITES

Group leader : Dr. Ana Rita GOMES

The Apicomplexa phylum comprises divergent single-celled eukaryotic organisms with significant clinical relevance, such as Plasmodium parasites, the causative agent of malaria. The pathogenicity of Plasmodium is, in part, linked to its high multiplication rate during vegetative growth within the human host.

Currently, we lack basic knowledge such as a clear definition of the parasite’s cell cycle, how it is regulated, how cell fate decisions are wired and to what extent general eukaryotic cell cycle principles apply to this organism. Unlike model organisms, Plasmodium divides in unconventional ways producing not two but dozens of daughter cells, in a single cell cycle round. During this cycle the parasite’s genomic content undergoes several DNA replication rounds, within an enclosed nucleus, after which newly formed, non-condensed, nuclei are segregated into daughter cells, in a process termed schizogony. In addition, Plasmodium lacks sex chromosomes and thus sex determination is non-genetic, with each haploid parasite capable of producing either a male or a female gametocyte in the human host.

Altogether this points to yet-to-be-explored original and divergent cell cycle and fate decision architectures in malaria parasites.

The overall goal of the lab is to understand cell cycle progression in malaria parasites and to dissect cell fate decisions. We aim to understand how cellular events of the Plasmodium cell cycle are coordinated and controlled during the intra erythrocytic stages of development. Understanding how these processes are orchestrated will not only shed light on how evolution has tailored this branch of the tree of life, but it will also potentiate the development of new anti-malarials.

Theme 3: Development of new compounds and evaluation of their antimalarial potential

Project 1: Development of purine analogues as potent antimalarial compounds.

PIs: Rachel Cerdan, Sharon Wein

We have identified a novel series of AcycloNucleoside Phosphonates (ANPs) with significant antimalarial activity in vitro against asexual blood stages and efficacy in vivo (P. vinckei- and P. berghei-infected mice). The lead compound shows an antimalarial activity in the nanomolar range with a very high selectivity index. ANPs are structurally unrelated to existing drugs and they have an original mode of action.

Our first objectives are:

to optimize the lead compound of this class and to design an orally administrable molecule that is suitable to be developed in the preclinical phase.
to assess the inhibitory potential of the compound on the different stages of the life cycle of the Plasmodium parasite.
to decipher its mode of action by identifying and validating its therapeutic target.

Project 2: Evaluation of a new principle of antimalarial strategy through the chemical activation of the host cell specific mechano-sensitive ion channel Piezo1.

PI: Kai Wengelnik

Piezo channels are mechanosensitive cation channels of higher eukaryotic organisms that are absent from Plasmodium species or other apicomplexan parasites. Red blood cells (RBCs) express only the Piezo1 channel. A link between Piezo1 function and malaria infection has first been shown using a mouse model. The protective phenotype has been linked to the hydration status of the RBCs. Most interestingly, this study also identified a new polymorphism in human Piezo1 that is very abundant in healthy people of African origin (about 30% of carriers). This polymorphism confers a reduction in RBC infection rates by P. falciparum in in vitro cultures. Currently very few compounds have been described to interfere with Piezo1 function, the most widely used being the Piezo1 activator Yoda1.

The aims of our project are the following:

Characterisation of the protective effect of Piezo1 activation through chemical stimulation on falciparum infection.
Identification and selection of new Piezo1 activators with potent antimalarial activity.
Evaluation whether the chemical activation of Piezo1 of the human RBC could serve as a new principle of antimalarial strategy since we are targeting a host cell protein and not the parasite itself.