Malaria, caused by Plasmodium parasites, is a devastating disease that is compounded by the growing emergence of parasite resistance to our most effective pharmaceuticals. Among those chemotherapies currently deployed, the endoperoxide antimalarial artemisinin is highly efficacious, yet the mechanism of action remains unresolved. Previous research efforts demonstrate that fluorescent trioxane derivatives localize to digestive vacuole-associated neutral lipid bodies of P. falciparum and application of artemisinin results in the oxidation of a fluorescent BODIPY peroxyl radical indicator probe in treated parasite populations. Recent evidence further suggests the involvement of phosphatidylinositol 3-phosphate and its associated kinase in artemisinin activity and resistance mechanisms. To explore the theory of artemisinin-induced lipid peroxidation further heme and artemisinin were reacted in the presence of a phosphatidylinositol lipid standard under acidic conditions that simulate the environment of the digestive vacuole. The resulting in vitro assay extracts were analyzed using standard analytical techniques. Here we report the first evidence of a novel fluorescent product resulting from the formation of heme-artemisinin adducts in the context of a phosphatidylinositol environment; thus further supporting lipid peroxidation as a potential mechanism of artemisinin in the parasite.

Investigating the mechanism of heme-activated artemisin metabolites through a lipid-based in vitro assay

251st National Meeting (2016)

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