Keywords: Malaria; aquaglyceroporin; assay systems; drug development
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.
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.
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.
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.
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.
University of Kiel, Pharmaceutical Institue
Dept. of Pharmaceutical Chemistry
Gutenbergstr. 76, D-24118 Kiel
Tel: +49 431 880 1809 (or 1131 secr.)
Fax: +49 431 880 1352
|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
|Tel: +46 31 773 2595, |
Fax: +46 31 773 2599,
|3||Sabine Flitsch||University of Edinburgh, School of Chemistry |
West Mains Road
UK-EH9 3JJ Edinburgh
|Tel: +44 131 650 4737 |
Fax: +44 131 650 4737
|4||Helmut Grubmüller||MPI, Department of Theoretical and Computational Biophysics |
Am Fassberg 11
|Tel: +49 551 201 2301 |
Fax: +49 551 201 2302
|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