Inhibition of hemozoin formation in Plasmodium falciparum trophozoite extracts by heme analogs: possible implication in the resistance to malaria conferred by the beta-thalassemia trait.

摘要: Human falciparum malaria, caused by the intracellular protozoa Plasmodium falciparum, results in 1–2 million deaths per year. P. digests host erythrocyte hemoglobin within its food vacuole, resulting release of potentially toxic free heme. A parasite-specific heme polymerization activity detoxifies cross-linking monomers to form hemozoin or malaria pigment. This biochemical process is target widely successful antimalarial drug chloroquine, which rapidly losing effectiveness due spread chloroquine resistance. We have shown that resistance not changes overall catalytic sensitivity. Therefore, remains a potential for novel antimalarials. In this study, we investigated ability analogs inhibit and parasite growth erythrocytes. Incorporation radioactive hemin substrate into an insoluble pellet was used determine polymerization. hypoxanthine nucleic add dividing parasites effects on growth. Microscopic measurements were made extent analog entry infected The tin protoporphyrin IX (SnPP), zinc (ZnPP), deuteroporphyrin IX, 2,4 bisglycol (ZnBG) inhibited at micromolar concentrations (ZnPP ≪ SnPP < ZnBG). However, they did since failed gain access site polymerization, parasite’s vacuole. Finally, observed high ZnPP levels erythrocytes from two patients with β-thalassemia trait, may tested able formation trophozite extracts. increased found thalassemic suggest these contribute, least part, protection conferred trait. finding lead development new forms therapy.