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Validation of the Plasmodium aquaglyceroporin as a drug target

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Can we fight malaria with chemotherapy?

Malaria is responsible for between 1 million and 2 million deaths worldwide every year and resistance to anti-malarial drugs is escalating. Novel strategies are sorely needed and one such approach has increased our chances of eventually controlling the disease.

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The 'Validation of the Plasmodium aquaglyceroporin as a drug target' (Malariaporin) project investigated an alternative approach to attacking the malaria parasite: from the outside rather than through the intracellular compartment. The EU-funded project intended to determine if this provided an improved means of overcoming rapid resistance so as to translate genomic information to drug development. The main question was whether the parasite/host interface's aquaglyceroporin (the Plasmodium water and glycerol channel) is a suitable drug target for chemotherapy. Researchers used their analyses of Plasmodium falciparum genome data to identify a single water/glycerol channel, PfAQP. This is the only member of the aquaporin family encoded in the P. falciparum genome. The PfAQP protein belongs to the major facilitator superfamily for nutrients and metabolites, and has high permeability for water and glycerol. Immunolabelling showed its presence at the parasite/host interface. Being a component of the reduced interface, the channel is a strong indicator for basic functions in the parasite's biochemistry and may play an important role in at least three vital cellular processes: protecting against osmotic stress, providing access to the serum glycerol pool before lipid synthesis, and offering glycerol uptake and oxidation so as to cope with oxidative stress. Major Malariaporin achievements include enhancing knowledge of the physiological role of aquaglyceroporins in plasmodia, identifying aquaporin protein structures involved in inhibitor binding and optimising the means for testing potential aquaporin blockers. Project partners also created novel lead compounds for anti-malarial chemotherapy. Developments in these areas open the way to devising futures strategies for assessing the role of aquaporins in pathogenic parasites and their potential use as drug targets.

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