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VITBIOMAL


Malaria

Vitamin Biosynthesis as a Target for Antimalarial Therapy
Framework programme:
6
Call:
2
Project number:
LSHP-CT-2005-012158
EC contribution:
€ 1,000,000
Duration:
24 months
Type:
STREP
Starting date:
1 June 2005

Keywords: Malaria; Plasmodium falciparum; vitamine biosynthesis; vitamin B6; drug; target; antimalarial drug development

Summary:

Plasmodium falciparum causes severe malaria and about 2 million human deaths annually. The main obstacle to combat the disease is increasing resistance of the parasites to existing drugs and the lack of a protective vaccine. Therefore, it is imperative that new suitable drug targets in the parasite`s metabolism are identified, assessed and validated. The availability of the parasite`s genome sequence offers an excellent tool to identify metabolic pathways potentially essential for parasite survival. Scrutinising the Plasmodium genomes revealed that they possess biosynthetic pathways for vitamins. Vitamins are organic compounds required in small amounts to ensure normal metabolic functions. Since they are not synthesised by humans, they need to be supplied via nutrients in trace amounts. The absence of vitamin biosynthesis in humans suggests that specific targeting of these parasite pathways with inhibitors is feasible. Thus, vitamin biosynthesis of Plasmodium might offer excellent potential for the development of novel chemotherapeutics against malaria with specific toxicity towards the parasites without affecting the host’s metabolism. In the first instance, we will focus on vitamin B6 biosynthesis, as this important nutrient is required as a co-factor for a wide variety of essential metabolic functions in protein and amino acid metabolism, and has also has been implicated in the defence against oxidative stress in other eukaryotes. Using reverse genetic approaches, we will validate the suitability of two of the vitamin B6 synthesising enzymes Pdx1 and Pdx2 respectively as drug targets. In addition, their precise biological functions and potential interactions with other cellular components will be analysed. Further, the biochemical, biophysical and structural features of both enzymes will be assessed in order to be able to rationally design specific inhibitors that interfere with the parasite’s proteins activities and functions.

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