Summary:

MalariaPorin is an interdisciplinary project that wants to evaluate the suitability of the single aquaglyceroporin of the parasite-host-interface as a novel drug target.

Background:

Malaria is one of the three major infectious diseases. Although the disease is prevalent in the tropics and sub-tropics, it has caused a global emergency. Three to four hundred 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.

Aim:

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. At the same time, the conditions for generating aquaglyceroporin inhibitory drugs are to be developed.

Expected results:

To achieve these goals, a multidisciplinary approach will be taken. This will cover 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.

Potential applications:

It is envisioned that MalariaPorin may become the starting point for developing new antimalarial drugs as well as 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.

Coordinator:

Partners:

Nº	Principal Scientific Participants	Official Address	Other Information
2	Stefan Hohmann	Götteborg University, Department of Cell and Molecular Biology/Microbiology PO Box 462, Medicinaregatan 9E SE- 405 30 Göteborg Sweden	Tel: +46 31 773 2595, Fax: +46 31 773 2599, E-mail: hohmann@gmm.gu.se
3	Sabine Flitsch	University of Edinburgh, School of Chemistry King’s Buildings West Mains Road UK-EH9 3JJ Edinburgh United Kingdom	Tel: +44 131 650 4737 Fax: +44 131 650 4737 E-mail: S.Flitsch@ed.ac.uk
4	Helmut Grubmüller	MPI, Department of Theoretical and Computational Biophysics Am Fassberg 11 DE-37077 Göttingen Germany	Tel: +49 551 201 2301 Fax: +49 551 201 2302 E-mail: hgrubmu@gwdg.de
5	Peter Agre	Johns-Hopkins University School of Medicine Department of Biological Chemistry 725 N. Wolfe Street Baltimore, MD 21205 United States of America	Tel: +1 410 955 7049 Fax: +1 410 955 3149 E-mail: pagre@jhmi.edu