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NOVEL ANTIMALARIALS


Malaria

Malarial Chemotherapy Targeting Plasmodial Phospholipid Biosynthesis: Implementation of a Pro-drug Strategy for Orally Active Compounds
Framework programme:
5
Project number:
QLK2-CT-2000-01166
EC contribution:
€ 1 450 000
Duration:
36 months
Type:
RS
Starting date:
1 January 2001

Keywords: Phospholipid metabolism; anti-phospholipid; malaria chemotherapy; development pharmacology; phospholipid; inhibitors; Plasmodium falciparum; Plasmodium vivax; Babesia

Summary:

The objective of this proposal is to develop a promising antimalarial drug that targets membrane biogenesis of the erythrocytic stage of malaria parasites. Phospholipid synthesis of the parasite, but not the host, is specifically blocked, and multiresistant malaria is susceptible to the compounds. To date no resistance has been found. This innovative development of new chemical weapons against malaria, capitalises on groundbreaking original work, and brings together a unique partnership of resources and expertise. The work proposed here has real prospects of delivering first-line, original antimalarial drugs as cheap replacements for chloroquine in areas of resistance.
Currently promising pro-drugs will be optimised and one candidate selected for rapid transfer to preclinical studies. Complementary research will define the molecular mechanisms of drug activity and will more fully characterise parasite serine lipid metabolism. This is an attractive pathway for drug development that is absent in mammalian cells and that offers considerable potential for medium-term pharmacological interventions.

Problem:

The impact of malaria on world health is enormous. The global threat of multidrug resistant malaria makes it imperative for a  rapid clinical assessment of promising new therapeutics. In fact, no current compound provides protection against malaria in all regions of the world. Drug development efforts must aim at obtaining compounds that work through new, independent mechanisms of action that are structurally unrelated to existing antimalarial agents.

Phospholipid biosynthesis of Plasmodium during its intraerythrocytic cycle is essential and now constitutes a validated and original pharmacological target.

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