Potential New Antimalarial Chemotherapeutics Based on Sphingolipid Metabolism

Abstract

The discovery of new antimalarial drugs is mandatory to improve the effectiveness of antimalarial prophylaxis and treatment. In this review, we focused on sphingolipids as potential new targets for antimalarial drugs. Inhibition of sphingomyelin and/or glucosylceramide synthases leads to increased intracellular concentrations of ceramide and results in growth inhibition of Plasmodium falciparum. In mammalian cells, ceramide mediates death by chemotherapeutic drugs. We demonstrated that ceramide mediates the antimalarial effect of artemisinin and mefloquine by depletion of glutathione levels. Furthermore, ceramide and artemisinin activated p38 mitogen-activated protein kinase in P. falciparum, thus inhibiting its growth, apparently by a non-apoptotic mechanism. In summary, we propose novel options of antimalarials based on ceramide cytotoxic activity.

Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes

“…Enzymes involved in phosphatidylcholine biosynthesis, which are thought to include the targets of bis-thiazolium drugs (Wengelnik et al., 2002) were associated with severely reduced growth (p < 0.05). In marked contrast, although Plasmodium blood stages can synthesize sphingolipids de novo and the pathway has been proposed for drug development (Pankova-Kholmyansky and Flescher, 2006), none of the implicated genes were important for normal growth in vivo, suggesting that sphingolipids may be scavenged from the host (p < 0.02).…”

Sphingolipids in Parasitic Protozoa

“…Together, these findings suggest SL metabolism could provide targets for new antimalarial drugs. Indeed, ceramide analogs including PPMP and PDMP have shown potent anti- P. falciparum activity in vitro , although their mechanism of action is still under investigation 72, 73.…”

Biosynthesis and Immunogenicity of Glucosylceramide in Cryptococcus neoformans and Other Human Pathogens

“…Interestingly, ganglioside presence in Entamoeba histolytica has been associated with possible antibodies found in patients with amoebiasis (85). It is also important that GSLs have been found in Plasmodium falciparum, and new therapy involves targeting GCS as antimalarial therapy, which has been shown to inhibit the growth of this intracellular protozoan in vitro (29,73).…”