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

Skinner-Adams, TS; Lowther, J; Teuscher, F; Stack, CM; Grembecka, J; Mucha, A; Kafarski, P; Trenholme, KR; Dalton, JP; Gardiner, DL

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

Skinner-Adams, TS Lowther, J Teuscher, F Stack, CM Grembecka, J Mucha, A Kafarski, P Trenholme, KR Dalton, JP Gardiner, DL

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Publication Type:: Journal Article
Citation:: Journal of Medicinal Chemistry, 2007, 50 (24), pp. 6024 - 6031
Issue Date:: 2007-11-29

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Field	Value	Language
dc.contributor.author	Skinner-Adams, TS	en_US
dc.contributor.author	Lowther, J	en_US
dc.contributor.author	Teuscher, F	en_US
dc.contributor.author	Stack, CM	en_US
dc.contributor.author	Grembecka, J	en_US
dc.contributor.author	Mucha, A	en_US
dc.contributor.author	Kafarski, P	en_US
dc.contributor.author	Trenholme, KR	en_US
dc.contributor.author	Dalton, JP	en_US
dc.contributor.author	Gardiner, DL	en_US
dc.date.issued	2007-11-29	en_US
dc.identifier.citation	Journal of Medicinal Chemistry, 2007, 50 (24), pp. 6024 - 6031	en_US
dc.identifier.issn	0022-2623	en_US
dc.identifier.uri	http://hdl.handle.net/10453/3534
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[CH 2]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 μM, 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. © 2007 American Chemical Society.	en_US
dc.relation.ispartof	Journal of Medicinal Chemistry	en_US
dc.relation.isbasedon	10.1021/jm070733v	en_US
dc.subject.classification	Medicinal & Biomolecular Chemistry	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Plasmodium chabaudi	en_US
dc.subject.mesh	Plasmodium falciparum	en_US
dc.subject.mesh	Phosphinic Acids	en_US
dc.subject.mesh	Leucyl Aminopeptidase	en_US
dc.subject.mesh	Leucine	en_US
dc.subject.mesh	Dipeptides	en_US
dc.subject.mesh	Recombinant Proteins	en_US
dc.subject.mesh	Antimalarials	en_US
dc.subject.mesh	Amino Acid Sequence	en_US
dc.subject.mesh	Structure-Activity Relationship	en_US
dc.subject.mesh	Kinetics	en_US
dc.subject.mesh	Models, Molecular	en_US
dc.subject.mesh	Molecular Sequence Data	en_US
dc.title	Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds	en_US
dc.type	Journal Article
utslib.citation.volume	24	en_US
utslib.citation.volume	50	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
utslib.for	0305 Organic Chemistry	en_US
dc.location.activity	ISI:000251181900019	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	24	en_US
pubs.publication-status	Published	en_US
pubs.volume	50	en_US

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[CH 2]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 μM, 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. © 2007 American Chemical Society.

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http://hdl.handle.net/10453/3534