Anti-Plasmodiumactivity of ceramide analogs

Labaied Mehdi, Dagan Arie, Dellinger Marc, Gèze Marc, Egée Stéphane, Thomas, Wang Chunbo, Gatt Shimon, Grellier, Grellier Philippe

Description

Sphingolipids are key molecules regulating many essential functions in eukaryotic cells and ceramide plays a central role in sphingolipid metabolism. A sphingolipid metabolism occurs in the intraerythrocytic stages of Plasmodium falciparum and is associated with essential biological processes. It constitutes an attractive and potential target for the development of new antimalarial drugs. Methods The anti- Plasmodium activity of a series of ceramide analogs containing different linkages (amide, methylene or thiourea linkages) between the fatty acid part of ceramide and the sphingoid core was investigated in culture and compared to the sphingolipid analog PPMP (d,1-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol). This analog is known to inhibit the parasite sphingomyelin synthase activity and block parasite development by preventing the formation of the tubovesicular network that extends from the parasitophorous vacuole to the red cell membrane and delivers essential extracellular nutrients to the parasite. Results Analogs containing methylene linkage showed a considerably higher anti- Plasmodium activity (IC 50 in the low nanomolar range) than PPMP and their counterparts with a natural amide linkage (IC 50 in the micromolar range). The methylene analogs blocked irreversibly P. falciparum development leading to parasite eradication in contrast to PPMP whose effect is cytostatic. A high sensitivity of action towards the parasite was observed when compared to their effect on the human MRC-5 cell growth. The toxicity towards parasites did not correlate with the inhibition by methylene analogs of the parasite sphingomyelin synthase activity and the tubovesicular network formation, indicating that this enzyme is not their primary target. Conclusions It has been shown that ceramide analogs were potent inhibitors of P. falciparum growth in culture. Interestingly, the nature of the linkage between the fatty acid part and the sphingoid core considerably influences the antiplasmodial activity and the selectivity of analogs when compared to their cytotoxicity on mammalian cells. By comparison with their inhibitory effect on cancer cell growth, the ceramide analogs might inhibit P. falciparum growth through modulation of the endogenous ceramide level.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2004
• Nombre de lectures: 7
• Langue: English

Extrait

Malaria Journal

BioMedCentral

Open Access Research Anti-Plasmodiumactivity of ceramide analogs 1 21 13 Mehdi Labaied, Arie Dagan, Marc Dellinger, Marc Gèze, Stéphane Egée, 3 22 1 Serge L Thomas, Chunbo Wang, Shimon Gattand Philippe Grellier*

1 Address: USM0504Biologie fonctionnelle des protozoaires, Département Régulations, Développement, Diversité Moléculaire, Muséum National 2 d'Histoire Naturelle, Boite postale n°52, 61 rue Buffon, 75231 Paris Cedex 05, France,Department of Biochemistry, Hebrew UniversityHadassah 3 School of Medicine, P.O. Box 12272, Jerusalem, 91120, Israel andCNRS FRE 2775, Station biologique de Roscoff, 29682 Roscoff, France

Email: Mehdi Labaied  [e-mail]; Arie Dagan  [e-mail]; Marc Dellinger  [e-mail]; Marc Gèze  [e-mail]; Stéphane Egée  egee@sbroscoff.fr; Serge L Thomas  thomas@sbroscoff.fr; Chunbo Wang  [e-mail]; Shimon Gatt  [e-mail]; Philippe Grellier*  [e-mail] * Corresponding author

Published: 10 December 2004Received: 30 October 2004 Accepted: 10 December 2004 Malaria Journal2004,3:49 doi:10.1186/1475-2875-3-49 This article is available from: http://www.malariajournal.com/content/3/1/49 © 2004 Labaied et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Background:Sphingolipids are key molecules regulating many essential functions in eukaryotic cells and ceramide plays a central role in sphingolipid metabolism. A sphingolipid metabolism occurs in the intraerythrocytic stages ofPlasmodium falciparumand is associated with essential biological processes. It constitutes an attractive and potential target for the development of new antimalarial drugs.

Methods:The anti-Plasmodiumactivity of a series of ceramide analogs containing different linkages (amide, methylene or thiourea linkages) between the fatty acid part of ceramide and the sphingoid core was investigated in culture and compared to the sphingolipid analog PPMP (d,1-threo-1-phenyl-2- palmitoylamino-3-morpholino-1-propanol). This analog is known to inhibit the parasite sphingomyelin synthase activity and block parasite development by preventing the formation of the tubovesicular network that extends from the parasitophorous vacuole to the red cell membrane and delivers essential extracellular nutrients to the parasite.

Results:Analogs containing methylene linkage showed a considerably higher anti-Plasmodiumactivity (IC 50 in the low nanomolar range) than PPMP and their counterparts with a natural amide linkage (ICin the 50 micromolar range). The methylene analogs blocked irreversiblyP. falciparumdevelopment leading to parasite eradication in contrast to PPMP whose effect is cytostatic. A high sensitivity of action towards the parasite was observed when compared to their effect on the human MRC-5 cell growth. The toxicity towards parasites did not correlate with the inhibition by methylene analogs of the parasite sphingomyelin synthase activity and the tubovesicular network formation, indicating that this enzyme is not their primary target.

Conclusions:It has been shown that ceramide analogs were potent inhibitors ofP. falciparumgrowth in culture. Interestingly, the nature of the linkage between the fatty acid part and the sphingoid core considerably influences the antiplasmodial activity and the selectivity of analogs when compared to their cytotoxicity on mammalian cells. By comparison with their inhibitory effect on cancer cell growth, the ceramide analogs might inhibitP. falciparumgrowth through modulation of the endogenous ceramide level.

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