title: Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds.
abstract: Previous studies have pinpointed the M17 leucyl aminopeptidase of Plasmodium falciparum (PfLAP) as a target for the development of new antimalarials. This metallo-exopeptidase functions in the terminal stages of hemoglobin digestion and is inhibited by bestatin, a natural analog of Phe-Leu. By screening novel phosphinate dipeptide analogues for inhibitory activity against recombinant PfLAP, we have discovered two compounds, 4 (hPheP[CH2]Phe) and 5 (hPheP[CH2]Tyr), with inhibitory constants better than bestatin. These compounds are fast, tight-binding inhibitors that make improved contacts within the active site of PfLAP. Both compounds inhibit the growth of P. falciparum in vitro, exhibiting IC50 values against the chloroquine-resistant clone Dd2 of 20-40 and 12-23 muM, respectively. While bestatin exhibited some in vivo activity against Plasmodium chabaudi chabaudi, compound 4 reduced parasite burden by 92%. These studies establish the PfLAP as a prime target for the development of antimalarial drugs and provide important new lead compounds.
authors.affiliation: Malaria Biology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4029, Australia.
authors.forename: Tina S
authors.initials: TS
authors.lastname: Skinner-Adams
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lowther
authors.forename: Franka
authors.initials: F
authors.lastname: Teuscher
authors.forename: Colin M
authors.initials: CM
authors.lastname: Stack
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.forename: Artur
authors.initials: A
authors.lastname: Mucha
authors.forename: Pawel
authors.initials: P
authors.lastname: Kafarski
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Trenholme
authors.forename: John P
authors.initials: JP
authors.lastname: Dalton
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gardiner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016788:Plasmodium chabaudi / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004151:Dipeptides; D010721:Phosphinic Acids; D011994:Recombinant Proteins; D007931:Leucyl Aminopeptidase; D007930:Leucine; C012211:ubenimex