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Contenido archivado el 2024-04-19

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

Objetivo



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.

Tema(s)

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Convocatoria de propuestas

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Régimen de financiación

CSC - Cost-sharing contracts

Coordinador

Université de Montpellier 1
Aportación de la UE
Sin datos
Dirección
Place Eugène Bataillon
34095 Montpellier
Francia

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Coste total
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Participantes (6)