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NOVEL ANTIMALARIALS
MALARIA
Framework programme: 5
Project number:
QLK2-CT-2000-01166
EC contribution: € 1 450 000
Duration: 36 months
Type: RS
Starting date: 1 January 2001
Graphic element Malarial Chemotherapy Targeting Plasmodial Phospholipid Biosynthesis: Implementation of a Pro-drug Strategy for Orally Active Compounds
Keywords: Phospholipid metabolism; anti-phospholipid; malaria chemotherapy; development pharmacology; phospholipid; inhibitors; Plasmodium falciparum; Plasmodium vivax; Babesia

Summary:

The objective of this proposal is to develop a promising antimalarial drug that targets membrane biogenesis of the erythrocytic stage of malaria parasites. Phospholipid synthesis of the parasite, but not the host, is specifically blocked, and multiresistant malaria is susceptible to the compounds. To date no resistance has been found. This innovative development of new chemical weapons against malaria, capitalises on groundbreaking original work, and brings together a unique partnership of resources and expertise. The work proposed here has real prospects of delivering first-line, original antimalarial drugs as cheap replacements for chloroquine in areas of resistance.
Currently promising pro-drugs will be optimised and one candidate selected for rapid transfer to preclinical studies. Complementary research will define the molecular mechanisms of drug activity and will more fully characterise parasite serine lipid metabolism. This is an attractive pathway for drug development that is absent in mammalian cells and that offers considerable potential for medium-term pharmacological interventions.

Problem:

The impact of malaria on world health is enormous. The global threat of multidrug resistant malaria makes it imperative for a  rapid clinical assessment of promising new therapeutics. In fact, no current compound provides protection against malaria in all regions of the world. Drug development efforts must aim at obtaining compounds that work through new, independent mechanisms of action that are structurally unrelated to existing antimalarial agents.

Phospholipid biosynthesis of Plasmodium during its intraerythrocytic cycle is essential and now constitutes a validated and original pharmacological target.

Aim:

One highly promising approach, targeting phopholipid synthesis pathways unique to the parasite, has identified a new class of drugs.  These disrupt membrane biogenesis, probably by interfering with choline transport. Promising efficacy (including multidrug resistant Plasmodium falciparum) and tolerance data in mice, dogs, and primates encourage rapid development for clinical testing.  Broadly useful antimalarials must be suitable for oral (rectal) use.  This is often a major hurdle in drug development.  Recently, a pro-drug approach has facilitated oral delivery of this class of compounds.  Here this strategy will be optimised and undertake critical preclinical studies.  Other critical lipid pathways are also absent in mammalian cells.  Complementary research will characterise these essential parasite activities and develop assays for novel drug selection

This programme concerns a new chemotherapy for P. falciparum and P. vivax malaria that targets membrane biogenesis of the erythrocytic stage of the parasite. The most promising drug interference is blockage of the choline transporter, a rate-limiting step in phosphatidycholine synthesis and an essential step for intraerythrocytic growth of the malaria parasite. Here the consortium will focus on the following major points:

1) Synthesis of pro-drugs to obviate the weak oral absorption of bis-cationic compounds and to promote the development of a new generation of effectors. The concept has been validated. This includes optimisation of two series, which satisfied the criteria for transfer to preclinical studies, and assessment of two other new delivery systems. Oral absorption and physical properties of the compounds will be maximised.
2) Characterisation of the interaction of the compounds with the infected erythrocyte (this project has recently shown that compounds are specifically accumulated at least 100-fold in the infected erythrocytes). This requires the synthesis of radio- and fluorescent-labelled compound derivatives of both bioprecursors and drugs.
3) Identification, isolation and characterisation of the intrinsically efficient drug target as a prerequisite to intracellular characterisation and a more rationale design of potent specific effectors.
4) Studies on the regulation of phospholipid metabolism and mechanisms involved in possible acquisition of resistance. Unique characteristics of serine-based lipid metabolism should provide further targets for development of new therapeutic agents.
5) Thorough studies of biological and pharmacological activities, including chemosensitivity of multiresistant malaria, therapeutic index after oral formulations in mouse and monkeys, and toxic evaluation of lead compounds.
6) Determination of pharmacokinetics and toxic properties in animals and their metabolisation for one compound under GMP and GLP procedures (as part of preclinical studies).

Expected results:

Synthesis and optimisation of three validated pro-drug systems, their physico-chemical characterisation, thorough evaluation of antimalarial activities, toxicity and pharmacokinetics in animals, selection of two molecules, scale up for the chemical synthesis, and setting up predevelopment studies. Complementary research will define the molecular mechanisms of drug activity and will more fully characterise parasite serine lipid metabolism.  This is an attractive pathway for drug development that is absent in mammalian cells and that offers considerable potential for medium-term pharmacological interventions.

Potential applications:

The major aim of the R&D proposed here is to develop orally prescribable antimalarial compounds (third generation) to the preclinical stage. This will promote pharmacological and industrial application. This will have a clear positive economic and social impact, which will benefit the European citizen and people from developing countries and meets the objectives of the specific Key Actions 2. Specific new therapeutics and patents are also anticipated.

Coordinator:

Henri Vial
UMR CNRS 5539
Dynamique Moléculaire des Interactions Membranaires
Département Biologie et Santé, Université Montpellier II, CC 107
Place Eugène Bataillon
34095 Montpellier Cedex 05
France
Tel: +33 4 67 14 37 45
Fax: +33 4 67 14 42 86
E-mail: vial@univ-montp2.fr

Partners:

Principal
Scientific
Participants
Official Address Other Information
2Michèle CalasAmino Acids
Peptides and Proteins Laboratory
University Montpellier II, cc22
Place Eugène Bataillon
FR-34095 Montpellier Cedex 05
France
Tel : +33 4 67 14 38 17
Fax : +33 4 67 14 48 66
E-mail: mcalas@univ-montp2.fr
3Steve WardPharmacology Research Labs
70 Pembroke Place Floor 1, Block H
UK-L69 3GE Liverpool
United Kingdom
Tel: +44 151 794 8219
Fax: +44 151 794 8217
E-mail: saward@liverpool.ac.uk
4Alan ThomasDepartment of Parasitology
Biomedical Research Centre
Postbox 3306
Lange Kleiweg 139
NL-2280 GH Rijswijk
The Netherlands
Tel: +31 15 842538
Fax: +31 15 84 3986
E-mail: thomas@bprc.nl
5Françoise BressolleLaboratoire de Pharmacocinétique Clinique
Faculté de Pharmacie
15 Avenue Charles Flahault
FR-34060 Montpellier Cedex 2
France
Tel: +33 4 67 54 80 75
Fax: +33 4 67 54 80 75
E-mail: FBressolle@aol.com
6Socrates HerreraFundacion Centro de Primates
Departamento de Microbiologia
Calle 4 b. N° 36-00AA 25574
Facultad de Salud
Universidad del Valle
Cali
Colombia
Tel: +57 25 58 1946
Fax: +57 25 58 1061
E-mail: soheva@mafalda.univalle.edu.co

 
 
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