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Agents antipaludeens agissant par perturbation du métabolisme phospholipidique. Développement d'un modèle pharmacologique

Objective



The availability of new pharmacological models will make possible to select antimalarial molecules With new mechanisms of action, thus delaying resistance. The approach is hinged on fundamental research started in 1980 to investigate the phospholipid metabolism of intraerythrocytic plasmodium that is abundant and indispensable for the production of its membranes. Any drug able to interfere With this metabolism blocks parasitic development. The most effective interference involves blockage of the choline transporter which is a limiting step in de novo synthesis of phosphatidylcholine. The compounds show antimalarial in vitro activity against P. falciparum at 1-10 nM, and in vivo, in the P. berghei or P. chabaudi/mouse System, at doses 20- to 100-times lower than their acute toxicity limit. The bioavailability shows a slow blood clearance and no significant concentration in tissues. The compounds are inexpensive to produce, stable and Water-soluble.
The present program aims to develop this pharmacological model as follows: 1) Biochemical studies of the pharmacological target, to find the causes of the hyperfunctioning of the choline carrier after malarial infection , morphological alterations of plasmodium induced by the drugs ;studies of' the criteria to optimize the structure of active compounds leading to lower intrinsic acute toxicity and better oral absorption 2) Synthesis of new molecules among the 3 hyperactive families With structure : activity relationships 3) To specify the antimalarial activity of the compounds in a broad spectrum of resistant strains or isolates in vitro and in vivo, and preclinical evaluation against P. falciparum in monkeys 4) Subcellular localization of radiolabelled lead compounds, and studies on their bioavailability and metabolism 5) determination on the ease by which parasites become resistant to the lead compounds in vitro and in Vivo 6) Research into the possible activities of the compounds against the non-erythrocvtic stage of plasmodium and of other potential activities 7) Toxicological Studies 8) Galenic studies of the lead compounds including ageing, oral absorption and duration of action.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Université de Montpellier 1
Address
Place Eugène Bataillon
34095 Montpellier
France

Participants (6)

Institut National de la Santé et de la Recherche Médicale (INSERM)
France
Address
369 Rue Jules Guesde
59650 Villeneuve-d'ascq
London School of Hygiene and Tropical Medicine
United Kingdom
Address
Keppel Street
WC1E 7HT London
Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek
Netherlands
Address
151,Lange Kleiweg
2280 HV Rijswijk
Organisation de Lutte Contre les Endémies en Afrique Centrale
Cameroon
Address

10 Yaoundé
UNIVERSIDAD DEL VALLE
Colombia
Address

0344406 Cali
Université de Montpellier II (Université des Sciences et Techniques du Languedoc)
France
Address
Place Eugène Bataillon
34095 Montpellier