title: Plasmodium falciparum: differential sensitivity in vitro to E-64 (cysteine protease inhibitor) and Pepstatin A (aspartyl protease inhibitor).
abstract: We investigated the effect of a cysteine proteinase inhibitor (E-64) and an aspartyl proteinase inhibitor (Pepstatin A) on asexual erythrocytic stages of Plasmodium falciparum in culture. These two protease inhibitors showed different patterns of activity. E-64 acted preferentially against trophozoite and schizont stages. After 48 h incubation at high concentrations of E-64 (28, 140, 280 microM), growth was totally abolished and the parasites presented characteristic enlarged food vacuoles. Morphological alterations were also seen after shorter incubation periods (6 h at 28 microM) or 12 h at the inhibitory concentration 50% (12 microM), but an additional culture period (24 h) in inhibitor-free medium allowed normal parasite development, demonstrating a parasitostatic effect. E-64 acts on parasite multiplication; the normal merozoite maturation was altered and the normal reinvasion process partially impaired. Pepstatin A used at the inhibitory concentration 50% (4 microM) killed the parasites before trophozoite development and had a major effect on schizonts maturation. No altered parasite development occurred during an additional culture period without Pepstatin A, demonstrating a parasiticidal effect. E-64 and Pepstatin A used in combination inhibit the parasite growth with a strong synergistic effect.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 13, Ancien Hôpital Claude Bernard, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Bailly
authors.forename: R
authors.initials: R
authors.lastname: Jambou
authors.forename: J
authors.initials: J
authors.lastname: Savel
authors.forename: G
authors.initials: G
authors.lastname: Jaureguiberry
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010436:Pepstatins / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D010436:Pepstatins; C014195:Streptomyces pepsin inhibitor; D016282:Aspartic Acid Endopeptidases; D007930:Leucine; C024974:E 64; C031375:pepstatin