Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds.

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Show simple item record Skinner-Adams, TS Lowther, J Teuscher, F Stack, CM Grembecka, J Mucha, A Kafarski, P Trenholme, KR Dalton, JP Gardiner, DL 2009-12-21T02:28:46Z 2007-11
dc.identifier.citation Journal of medicinal chemistry, 2007, 50 (24), pp. 6024 - 6031
dc.identifier.issn 0022-2623
dc.identifier.other C1 en_US
dc.description.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.
dc.format Print-Electronic
dc.language eng
dc.relation.isbasedon 10.1021/jm070733v
dc.title Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds.
dc.type Journal Article
dc.parent Journal of medicinal chemistry
dc.journal.volume 24
dc.journal.volume 50
dc.journal.number 24 en_US
dc.publocation Washington en_US
dc.identifier.startpage 6024 en_US
dc.identifier.endpage 6031 en_US i3 Investment Area Core Member en_US
dc.conference Verified OK en_US
dc.for 0304 Medicinal and Biomolecular Chemistry
dc.for 1115 Pharmacology and Pharmaceutical Sciences
dc.personcode 995262
dc.personcode 030896
dc.personcode 996591
dc.percentage 50 en_US Pharmacology and Pharmaceutical Sciences en_US
dc.classification.type FOR-08 en_US
dc.location.activity ISI:000251181900019 en_US
dc.description.keywords Animals
dc.description.keywords Plasmodium chabaudi
dc.description.keywords Plasmodium falciparum
dc.description.keywords Phosphinic Acids
dc.description.keywords Leucyl Aminopeptidase
dc.description.keywords Dipeptides
dc.description.keywords Recombinant Proteins
dc.description.keywords Kinetics
dc.description.keywords Amino Acid Sequence
dc.description.keywords Molecular Sequence Data
dc.description.keywords Leucine
dc.description.keywords Antimalarials
dc.description.keywords Models, Molecular
dc.description.keywords Structure-Activity Relationship
pubs.embargo.period Not known
pubs.organisational-group /University of Technology Sydney
pubs.organisational-group /University of Technology Sydney/Faculty of Science
utslib.copyright.status Closed Access 2015-04-15 12:17:09.805752+10
pubs.consider-herdc true
utslib.collection.history Closed (ID: 3)

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