Malaria Journal Anti-Plasmodium activity of ceramide analogs

• Published in: Malaria journal 2004, Vol.3
• Main Authors: Labaïed, Medhi, Dagan, A, Dellinger, Marc, Gèze, Marc, Egée, Stéphane, Thomas, S L, Wang, C, Gatt, S, Grellier, Philippe
• Format: Article
• Language: English
• Subjects: Chemical Sciences; Life Sciences; Microbiology and Parasitology
• ISSN: 1475-2875; 1475-2875
• DOI: 10.1186/1475-2875-3-49

Background: Sphingolipids are key molecules regulating many essential functions in eukaryotic cells andceramide plays a central role in sphingolipid metabolism. A sphingolipid metabolism occurs in theintraerythrocytic stages of Plasmodium falciparum and is associated with essential biological processes. Itconstitutes 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 wasinvestigated 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 sphingomyelinsynthase activity and block parasite development by preventing the formation of the tubovesicularnetwork 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 (IC50in the low nanomolar range) than PPMP and their counterparts with a natural amide linkage (IC50 in themicromolar range). The methylene analogs blocked irreversibly P. falciparum development leading toparasite eradication in contrast to PPMP whose effect is cytostatic. A high sensitivity of action towards theparasite was observed when compared to their effect on the human MRC-5 cell growth. The toxicitytowards parasites did not correlate with the inhibition by methylene analogs of the parasite sphingomyelinsynthase 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 inculture. Interestingly, the nature of the linkage between the fatty acid part and the sphingoid coreconsiderably influences the antiplasmodial activity and the selectivity of analogs when compared to theircytotoxicity on mammalian cells. By comparison with their inhibitory effect on cancer cell growth, theceramide analogs might inhibit P. falciparum growth through modulation of the endogenous ceramide level