MalariaPorin - Validation of the plasmodium aquaglyceroporin as a drug target
- EC contribution
- : € 885.600
- Duration
- : 27 months
- Starting date
- : 01/01/2005
- Funding scheme
- : Specific Targeted Research Project
- Keywords
- : malaria, aquaglyceroporin, assay systems, drug development
- Contract/Grant agreement number
- : LSHB-CT-2004-012189
- Project web-site:
- http://ec.europa.eu/research/health/poverty-diseases/projects/99_en.htm
Background:
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. Between 300 to 400 million cases with 1 million to 2 million deaths are recorded each year. A rapidly increasing resistance to antimalarial drugs calls for focused novel strategies on combating the disease.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.
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.
Problem:
The P. falciparum genome project aims at the accelerated discovery of novel antimalarial drug targets. Of particular interest are proteins of unusual metabolic pathways and of the parasite/host interface for metabolite exchange and ion homeostasis. Using P. falciparum genome data, the coordinator of MalariaPorin has identified a single water/glycerol channel (aquaglyceroporin, PfAQP) to be present at the parasite/host interface. It is furthermore the only member of the aquaporin family encoded in the P. falciparum genome. The PfAQP protein belongs to the major facilitator super family for nutrients and metabolites and is a bi-functional pore with high permeability for water and glycerol. Apart from PfAQP, the parasite/host interface so far consists of only five further facilitators for monocarboxylates and nucleosides. Carrying a limited interface with the least possible number of membrane channels and transporters is typical for intracellular parasites. The fact, that the aquaglyceroporin is a component of the interface strongly suggests basic functions in the parasite biochemistry.
Aim:
PfAQP complies with important requirements for being used as a drug target for chemotherapy due to the likely involvement in basic systems of the parasite and to unique functional and structural properties. For these reasons we assess the suitability of PfAQP as an anti-malarial drug target and to generate the conditions for the further development of such drugs. 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.
Expected and obtained results:
Significant progress has been made in various areas related to the project. This involves fields as diverse as basic Plasmodium physiology, pharmaceutical chemistry, as well as biophysics. In more detail, MalariaPorin was set up to a) provide first insights into osmotic protection systems of apicomplexan, intracellular parasites, b) obtain fundamental and novel data on glycerol metabolism of P. falciparum, c) redefine known and specify new aquaporin protein structures that determine pore selectivity, d) identify therapeutically targetable aquaporin structures, e) establish solid and usable assay systems for testing potential aquaporin blockers, f) build a knowledge base for drug testing on aquaporins, g) refine known aquaporin blocking lead compounds, and h) yield novel lead structures for the inhibition of the P. falciparum aquaglyceroporin, which may be applicable as innovative antimalarial drugs.
Potential applications:
PfAQP has the potential to be used as a target for malaria treatment. It is further 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.
Coordinator:
University of Kiel
Pharmaceutical Institute
Gutenbergstrasse 76
24118 Kiel, Germany
Tel. +49 431 880 1809
Fax +49 431 880 1352
E-mail: ebeitz@pharmazie.uni-kiel.de
Partners:
University of Tübingen
Tübingen, Germany
Prof. Stefan Hohmann
University of Gothenburg
Gothenburg, Sweden
Prof. Sabine Flitsch
University of Manchester
Manchester, England, UK
Dr Bert de Groot and Dr Helmut Grubmüller
Max Planck Institute for Biophysical Chemistry
Göttingen, Germany
Prof. Peter Agre and Prof. Nirbhay Kumar
Johns-Hopkins University School of Medicine
Baltimore, Maryland, US