title: Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors.
abstract: The Plasmodium falciparum cysteine protease falcipain is required for the degradation of hemoglobin by erythrocytic malaria parasites. In prior studies, peptidyl inhibitors of falcipain blocked hemoglobin degradation and development by cultured parasites and one of these compounds, when administered parenterally, cured Plasmodium vinckei-infected mice. We now report an evaluation of orally administered peptidyl inhibitors of falcipain in a mouse malaria model. In studies with a fluoromethyl ketone, orally administered morpholine urea-phenylalanine-homophenylalanine-fluoromethyl ketone delayed the progression of murine malaria. In studies of a new series of vinyl sulfones, a set of related compounds demonstrated marked inhibition of falcipain and of parasite biological activities in vitro. One of these compounds, N-methyl piperazine urea-leucine-homophenylalanine-2-naphthalene vinyl sulfone, cured about 40% of mice when administered orally twice-a-day for four days. Our results suggest that peptidyl inhibitors of falcipain have promise as antimalarial chemotherapeutic agents.
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, 94143, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Olson
authors.forename: G K
authors.initials: GK
authors.lastname: Lee
authors.forename: A
authors.initials: A
authors.lastname: Semenov
authors.forename: P J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D013997:Time Factors
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D003546:Cysteine Endopeptidases; C099607:falcipain