Anti-Plasmodium activity of ceramide analogs

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 (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

Métabolisme des sphingolipides chez Plasmodium falciparum, agent du paludisme (Incidence chimiothérapeutique)

Plusieurs voies du métabolisme des sphingolipides ont été décrites chez Plasmodium falciparum, agent du paludisme, lors de son développement intraérythrocytaire : voie de synthèse de novo du céramide (Cer), voies de synthèse des glycosphingolipides et de la sphingomyéline (SM), et la voie d'hydrolyse de la SM. Ce métabolisme paraît être impliqué dans des processus fondamentaux pour le développement parasitaire. Nous avons réalisé une étude structure-activité d'analogues de Cer et de SM potentiellement inhibiteurs du développement de P. falciparum. Les analogues de Cer possédant une liaison méthylène liant l'azote de la structure sphingosyle à une chaine de 12-14 carbones sont les plus actifs avec des CI50 de 17-30 nM. Les activités SM synthase et sphingomyélinase (SMase) du parasite ne semblent pas être la cible de ces analogues. Les analogues de SM de type R-sphingosyl-phosphorylcholine inhibent également le développement parasitaire avec une CI50 de 0,3 æM pour le meilleur (analogue en liaison thiourée). Ces inhibiteurs semblent agir en inhibant l'activité SMase du parasite. Parallèlement, une approche bioinformatique nous a permis de caractériser le gène putatif de la SMase de P. falciparum. Au-delà de leur potentiel chimio-thérapeutique, ces analogues constituent des outils pour explorer le rôle du métabolisme des sphingolipides, et son importance chez P. falciparumSeveral sphingolipid pathways were described in Plasmodium falciparum, the malaria agent, during its intraerythrocytic stages : ceramide (Cer) de novo synthesis, glycosphingolipid and sphingomyelin (SM) synthesis, and SM hydrolysis. Metabolism of sphingolipids appears to be involved in fundamental processes for the parasite development. We realized a study of structure-activity relationships of Cer and SM analogues on the inhibition of the P. falciparum intraerythrocytic development. Among the Cer analogues tested, those presenting a methylene linkage between the amino group of sphingosyl skeleton and a 12-14 carbon chain, exhibit the best inhibitory activity with IC50s of 17-30 nM. Parasite SM synthase and sphingomyelinase (SMase) do not seem to be the target of these analogues. SM analogues of R-sphingosylphosphorylcholine type also inhibit the parasite development with IC50 of 0.3 æm for the best (analogue with a thiourea linkage). These inhibitors seem to act by inhibiting the parasite SMase. In parallel, we characterized the putative gene of the P. falciparum SMase. Beyond their chemotherapeutic potential, these analogues constitute useful tools to explore the role(s) of sphingolipid metabolism and its importance for P. falciparumPARIS-Museum Hist.Naturelle (751052304) / SudocSudocFranceF

Synthesis and Antimalarial Activity of Some New 1,2-Dioxolane Derivatives

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Nutrient Diagnosis Norms for Date Palm (Phoenix dactylifera L.) in Tunisian Oases

Several studies have pointed out the promising use of nutritional diagnosis methods for the determination of optimum nutrient contents in plant tissues. The present investigation was carried out in different oases in Southern Tunisia to determine reference values for the interpretation of leaf analyses of date palm (Phoenix dactylifera) Deglet Nour cultivar with the Critical Value Approach (CVA) and the Compositional Nutrient Diagnosis (CND). A database (n = 100) of yield and mineral concentrations taken from date palm leaflets in October, at the maturity stage of dates, was used. The yield cut-off between low-yield and high-yield subpopulations, selected from cumulative variance ratio functions across survey data, was 76 kg palm−1 and the global nutrient imbalance index (CNDr2) was 10.06. Critical CND nutrient indices were found to be symmetrical around zero as follows: (1.59; +1.59) for IN, (−0.44, +0.44) for IP, (−0.63, +0.63) for IK, (−0.94, +0.94) for ICa, (−1.05, +1.05) for IMg, (−0.80, +0.80) for IFe, (−0.74, +0.74) for ICu, (−0.80, +0.80) for IB, (−0.93, +0.93) for IZn, (−1.04, +1.04) for IMn, and (−1.03, +1.03) for the residual value. Compared to CND, the CVA approach shows weak detection of the nutrients that cause nutritional imbalance. CND indices revealed, except for N, the presence of nutrient imbalances and the necessity to correct the mineral nutrition of date palm in the Kebeli oases

Synthesis, Antimalarial Activity, and Molecular Modeling of New Pyrrolo[1,2- a ]quinoxalines, Bispyrrolo[1,2- a ]quinoxalines, Bispyrido[3,2- e ]pyrrolo[1,2- a ]pyrazines, and Bispyrrolo[1,2- a ]thieno[3,2- e ]pyrazines

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Genetically modified Plasmodium parasites as a protective experimental malaria vaccine.

Malaria is a mosquito-borne disease that is transmitted by inoculation of the Plasmodium parasite sporozoite stage. Sporozoites invade hepatocytes, transform into liver stages, and subsequent liver-stage development ultimately results in release of pathogenic merozoites. Liver stages of the parasite are a prime target for malaria vaccines because they can be completely eliminated by sterilizing immune responses, thereby preventing malarial infection. Using expression profiling, we previously identified genes that are only expressed in the pre-erythrocytic stages of the parasite. Here, we show by reverse genetics that one identified gene, UIS3 (upregulated in infective sporozoites gene 3), is essential for early liver-stage development. uis3-deficient sporozoites infect hepatocytes but are unable to establish blood-stage infections in vivo, and thus do not lead to disease. Immunization with uis3-deficient sporozoites confers complete protection against infectious sporozoite challenge in a rodent malaria model. This protection is sustained and stage specific. Our findings demonstrate that a safe and effective, genetically attenuated whole-organism malaria vaccine is possible