title: Stage-specific antimalarial activity of cysteine protease inhibitors.
abstract: Cysteine proteases of the malaria parasite Plasmodium falciparum, known as falcipains, are promising targets for antimalarial chemotherapy. We evaluated cultured parasites for the stage-specific expression of cysteine proteases and sensitivity to cysteine protease inhibitors. Protease activity and inhibitor sensitivity varied markedly over time. Cysteine protease activity was greatest in early trophozoites, while sensitivity to cysteine protease inhibitors was greatest in mature trophozoites. Our results indicate the importance of considering the stage-specific effects of antimalarials and are consistent with the conclusion that the principal antimalarial activity of cysteine protease inhibitors is due to a block in hemoglobin hydrolysis.
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, 94143, USA.
authors.forename: Bhaskar R
authors.initials: BR
authors.lastname: Shenai
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Semenov
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004912:Erythrocytes / Q000469:parasitology; D018507:Gene Expression Regulation, Developmental; D006454:Hemoglobins / Q000378:metabolism; D006868:Hydrolysis; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D013997:Time Factors
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D006454:Hemoglobins; D007976:Leupeptins; D003546:Cysteine Endopeptidases; C099607:falcipain; D007930:Leucine; C032854:leupeptin; C024974:E 64