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Validation of the Plasmodium aquaglyceroporin as a drug target

Objective

Malaria is one of the three major infectious diseases. Although the disease is prevalent in the tropics and subtropics it has caused a global emergency. 300-400 million cases with 1-2 million deaths per year and rapidly increasing resistance to antimalarial drugs call for focused novel strategies on combating malaria. Transport proteins for nutrients and metabolites of the minimal parasite/host interface are getting into the focus of the current search for novel antimalarial targets. MalariaPorin is an interdisciplinary project that wants to take genomic information to drug development. The chief goal is to decide on the question whether the Plasmodium water and glycerol channel, aquaglyceroporin, of the parasite/host interface is a suitable drug target for chemotherapy. Concurrently, the conditions for generating aquaglyceroporin inhibitory drugs are developed. To achieve these goals, a multidisciplinary approach is taken covering a) thorough studies on the physiological role of water and glycerol transport in the malaria parasite including the generation of deletion strains; b) establishment of robust and practical assay systems for compound testing based on Xenopus laevis oocytes, yeast and P. falciparum parasites; c) determination from field isolates of the occurrence and functional consequences of polymorphisms of the aquaglyceroporin gene; d) generation of protein structure models and elucidation of the 3D structure from protein crystallisation for solving mechanistic questions on the channel selectivity and for virtual drug design; e) design and synthesis of compound libraries based on the knowledge of other aquaporin blockers and biochemical studies of substrate specificity. It is envisioned that MalariaPorin may become the starting point for a wider strategy to assess the role of aquaporins in pathogenic parasites, such as Toxoplasma gondii and Trypanosoma brucei and cruzi, and their potential use as drug targets.

Call for proposal

FP6-2003-LIFESCIHEALTH-3
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Coordinator

CHRISTIAN-ALBRECHTS-UNIVERSITY OF KIEL
Address
Olshausenstr. 40
Kiel
Germany

Participants (6)

GOTEBORG UNIVERSITY
Sweden
Address
Vasaparken
100 Goteborg
THE UNIVERSITY OF EDINBURGH
United Kingdom
Address
Old College, South Bridge
Edinburgh
MAX-PLANCK-GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.
Germany
Address
Hofgartenstrasse 8
Muenchen
JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
United States
Address
725 N. Wolfe Street
Baltimore, Md
THE UNIVERSITY OF MANCHESTER
United Kingdom
Address
Oxford Road
Manchester
EBERHHARD-KARLS-UNIVERSITÄT TÜBINGEN
Germany
Address
Wilhelmstr. 5
Tuebingen