title: Chemical target validation studies of aminopeptidase in malaria parasites using alpha-aminoalkylphosphonate and phosphonopeptide inhibitors.
abstract: During its intraerythrocytic phase, the most lethal human malarial parasite, Plasmodium falciparum, digests host cell hemoglobin as a source of some of the amino acids required for its own protein synthesis. A number of parasite endopeptidases (including plasmepsins and falcipains) process the globin into small peptides. These peptides appear to be further digested to free amino acids by aminopeptidases, enzymes that catalyze the sequential cleavage of N-terminal amino acids from peptides. Aminopeptidases are classified into different evolutionary families according to their sequence motifs and preferred substrates. The aminopeptidase inhibitor bestatin can disrupt parasite development, suggesting that this group of enzymes might be a chemotherapeutic target. Two bestatin-susceptible aminopeptidase activities, associated with gene products belonging to the M1 and M17 families, have been described in blood-stage P. falciparum parasites, but it is not known whether one or both are required for parasite development. To establish whether inhibition of the M17 aminopeptidase is sufficient to confer antimalarial activity, we evaluated 35 aminoalkylphosphonate and phosphonopeptide compounds designed to be specific inhibitors of M17 aminopeptidases. The compounds had a range of activities against cultured P. falciparum parasites with 50% inhibitory concentrations down to 14 muM. Some of the compounds were also potent inhibitors of parasite aminopeptidase activity, though it appeared that many were capable of inhibiting the M1 as well as the M17 enzyme. There was a strong correlation between the potencies of the compounds against whole parasites and against the enzyme, suggesting that M17 and/or M1 aminopeptidases may be valid antimalarial drug targets.
authors.affiliation: Department of Microbiology, School of Genetics and Microbiology, Moyne Institute of Preventive Medicine, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Eithne
authors.initials: E
authors.lastname: Cunningham
authors.forename: Marcin
authors.initials: M
authors.lastname: Drag
authors.forename: Pawel
authors.initials: P
authors.lastname: Kafarski
authors.forename: Angus
authors.initials: A
authors.lastname: Bell
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D043384:Glutamyl Aminopeptidase; D006801:Humans; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011480:Protease Inhibitors / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D063065:Organophosphonates; D010455:Peptides; D011480:Protease Inhibitors; D000626:Aminopeptidases; D007931:Leucyl Aminopeptidase; D043384:Glutamyl Aminopeptidase