Study of the phospholipid metabolism and targeting of an essential enzyme of the malaria parasite. – PaluMet

Malaria is a major global health problem and the main parasitic endemic disease in the world. Recent progress in malaria control is again threatened by the parasite's resistance to the most effective drugs. The development of new antimalarial treatments involving new pharmacological targets remains a priority.
During its life cycle, the parasite develops in mosquitos and humans and the symptomatic phase of the disease corresponds to its massive multiplication in red blood cells. For its development and multiplication, the parasite relies on its phospholipid metabolism to meet the need for massive membrane biogenesis. The three main structural phospholipids of the parasite are essential for its survival and are synthesized through several connected pathways involving a dozen enzymes.
The PaluMet project focuses on the phospholipid metabolism of the malaria parasite. It aims at developing new potent inhibitors targeting the rate-limiting enzyme (the CCT) of the phosphatidylcholine pathway and at deciphering the complex and interconnected pathways of the phospholipid metabolism in order to identify new relevant therapeutic targets for future development.
To reach our objectives, a target-based approach for rationalized search for efficient and specific inhibitors will be applied to the CCT that we have already structurally characterized. Two types of enzyme ligands, compounds (MW> 250 Da) and fragments (MW< 250 Da), will be identified by screening for their ability to interact and/or to inhibit the target. Screening of ligands will be performed by biochemical techniques and by activity assays. 3D co-structures of the CCT in complex with inhibitors will be determined by X-ray crystallography and inhibitors will be optimized in an iterative and integrated process based on the 3D structures. The inhibitor compounds will be evaluated in vitro on human parasite lines and in vivo in malaria mouse models.
In parallel, we will map the complex and interconnected phospholipid pathways of the parasite and study the regulation between the different pathways. Analysis of metabolic intermediates and fluxes will determine the parasite’s adaptability in response to controlled disturbances (such as gene knock-down/knock-out or inhibitors). To this purpose, we will label simultaneously the precursors of the pathways, to follow and to quantify by lipidomics the final phospholipid products but also all the soluble intermediates. We want to assess offsetting effects from one pathway to another and to ultimately identify bottlenecks and critical steps.
This multidisciplinary project is planned for 3.5 years and is supported by a collaboration between three academic teams at the interface of health-biology, biochemistry, structural biology and chemistry. Together, the partners have the required know-how to carry out the project with a high level of complementarity combining expertise in malaria, phospholipid metabolism and drug screening (Partner 1), structural biology and drug design (Partner 2) and lipidomics by mass spectrometry (Partner 3).
A better understanding of the essential mechanisms of the phospholipid metabolism is of the utmost importance to meet the challenges of drug discovery in the malaria field. The program of the PaluMet project has been designed to this end and will pave the way for the development of a new antimalarial therapy.