title: Anti-Plasmodium activity of ceramide analogs.
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 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 (IC50 in the low nanomolar range) than PPMP and their counterparts with a natural amide linkage (IC50 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.
authors.affiliation: USM0504 Biologie fonctionnelle des protozoaires, Département Régulations, Développement, Diversité Moléculaire, Muséum National d'Histoire Naturelle, Boite postale 52, 61 rue Buffon, 75231 Paris Cedex 05, France. mehdi.labaied@sbri.org
authors.forename: Mehdi
authors.initials: M
authors.lastname: Labaied
authors.forename: Arie
authors.initials: A
authors.lastname: Dagan
authors.forename: Marc
authors.initials: M
authors.lastname: Dellinger
authors.forename: Marc
authors.initials: M
authors.lastname: Gèze
authors.forename: Stéphane
authors.initials: S
authors.lastname: Egée
authors.forename: Serge L
authors.initials: SL
authors.lastname: Thomas
authors.forename: Chunbo
authors.initials: C
authors.lastname: Wang
authors.forename: Shimon
authors.initials: S
authors.lastname: Gatt
authors.forename: Philippe
authors.initials: P
authors.lastname: Grellier
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002518:Ceramides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D008856:Microscopy, Fluorescence; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013107:Sphingolipids / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002518:Ceramides; D013107:Sphingolipids; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase