Identification of Phosphinate Dipeptide Analog Inhibitors Directed against the Plasmodium falciparum M17 Leucine Aminopeptidase as Lead Antimalarial Compounds
Identifieur interne : 001A71 ( Main/Exploration ); précédent : 001A70; suivant : 001A72Identification of Phosphinate Dipeptide Analog Inhibitors Directed against the Plasmodium falciparum M17 Leucine Aminopeptidase as Lead Antimalarial Compounds
Auteurs : Tina S. Skinner-Adams [Pologne] ; Jonathan Lowther [Pologne] ; Franka Teuscher [Pologne] ; Colin M. Stack [Pologne] ; Jolanta Grembecka [Pologne] ; Artur Mucha [Pologne] ; Pawel Kafarski [Pologne] ; Katharine R. Trenholme [Pologne] ; John P. Dalton [Pologne] ; Donald L. Gardiner [Pologne, Australie]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2007.
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 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.
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DOI: 10.1021/jm070733v
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Skinner-Adams</name><affiliation wicri:level="1"><country xml:lang="fr">Pologne</country><wicri:regionArea>Malaria Biology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland, 4029, Australia,Department of Medicine, Central Medical Division, University of Queensland, Brisbane, 4072, Australia, Institute for the Biotechnology ofInfectious Diseases, University of Technology Sydney, Corner of Thomas and Harris Street, Ultimo, Sydney, NSW 2007, Australia,Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22904, and Department ofBioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyspianskiego 27, 50-370 Wrocław</wicri:regionArea><wicri:noRegion>50-370 Wrocław</wicri:noRegion></affiliation><affiliation></affiliation><affiliation></affiliation></author><author><name sortKey="Lowther, Jonathan" sort="Lowther, Jonathan" uniqKey="Lowther J" first="Jonathan" last="Lowther">Jonathan Lowther</name><affiliation wicri:level="1"><country xml:lang="fr">Pologne</country><wicri:regionArea>Malaria Biology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland, 4029, Australia,Department of Medicine, Central Medical Division, University of Queensland, Brisbane, 4072, Australia, Institute for the Biotechnology ofInfectious Diseases, University of Technology Sydney, Corner of Thomas and Harris Street, Ultimo, Sydney, NSW 2007, Australia,Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22904, and Department ofBioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyspianskiego 27, 50-370 Wrocław</wicri:regionArea><wicri:noRegion>50-370 Wrocław</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Teuscher, Franka" sort="Teuscher, Franka" uniqKey="Teuscher F" first="Franka" last="Teuscher">Franka Teuscher</name><affiliation wicri:level="1"><country xml:lang="fr">Pologne</country><wicri:regionArea>Malaria Biology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland, 4029, Australia,Department of Medicine, Central Medical Division, University of Queensland, Brisbane, 4072, Australia, Institute for the Biotechnology ofInfectious Diseases, University of Technology Sydney, Corner of Thomas and Harris Street, Ultimo, Sydney, NSW 2007, Australia,Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22904, and Department ofBioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyspianskiego 27, 50-370 Wrocław</wicri:regionArea><wicri:noRegion>50-370 Wrocław</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Stack, Colin M" sort="Stack, Colin M" uniqKey="Stack C" first="Colin M." last="Stack">Colin M. 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Trenholme</name><affiliation wicri:level="1"><country xml:lang="fr">Pologne</country><wicri:regionArea>Malaria Biology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland, 4029, Australia,Department of Medicine, Central Medical Division, University of Queensland, Brisbane, 4072, Australia, Institute for the Biotechnology ofInfectious Diseases, University of Technology Sydney, Corner of Thomas and Harris Street, Ultimo, Sydney, NSW 2007, Australia,Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22904, and Department ofBioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyspianskiego 27, 50-370 Wrocław</wicri:regionArea><wicri:noRegion>50-370 Wrocław</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Dalton, John P" sort="Dalton, John P" uniqKey="Dalton J" first="John P." last="Dalton">John P. Dalton</name><affiliation wicri:level="1"><country xml:lang="fr">Pologne</country><wicri:regionArea>Malaria Biology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland, 4029, Australia,Department of Medicine, Central Medical Division, University of Queensland, Brisbane, 4072, Australia, Institute for the Biotechnology ofInfectious Diseases, University of Technology Sydney, Corner of Thomas and Harris Street, Ultimo, Sydney, NSW 2007, Australia,Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22904, and Department ofBioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyspianskiego 27, 50-370 Wrocław</wicri:regionArea><wicri:noRegion>50-370 Wrocław</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Gardiner, Donald L" sort="Gardiner, Donald L" uniqKey="Gardiner D" first="Donald L." last="Gardiner">Donald L. Gardiner</name><affiliation wicri:level="1"><country xml:lang="fr">Pologne</country><wicri:regionArea>Malaria Biology Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland, 4029, Australia,Department of Medicine, Central Medical Division, University of Queensland, Brisbane, 4072, Australia, Institute for the Biotechnology ofInfectious Diseases, University of Technology Sydney, Corner of Thomas and Harris Street, Ultimo, Sydney, NSW 2007, Australia,Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22904, and Department ofBioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyspianskiego 27, 50-370 Wrocław</wicri:regionArea><wicri:noRegion>50-370 Wrocław</wicri:noRegion></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Australie</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Medicinal Chemistry</title><title level="j" type="abbrev">J. Med. Chem.</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published" when="2007-10-26">2007</date><date when="2007-11-29">2007</date><biblScope unit="vol">50</biblScope><biblScope unit="issue">24</biblScope><biblScope unit="page" from="6024">6024</biblScope><biblScope unit="page" to="6031">6031</biblScope></imprint><idno type="ISSN">0022-2623</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="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 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.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Pologne</li></country></list><tree><country name="Pologne"><noRegion><name sortKey="Skinner Adams, Tina S" sort="Skinner Adams, Tina S" uniqKey="Skinner Adams T" first="Tina S." last="Skinner-Adams">Tina S. Skinner-Adams</name></noRegion><name sortKey="Dalton, John P" sort="Dalton, John P" uniqKey="Dalton J" first="John P." last="Dalton">John P. Dalton</name><name sortKey="Gardiner, Donald L" sort="Gardiner, Donald L" uniqKey="Gardiner D" first="Donald L." last="Gardiner">Donald L. Gardiner</name><name sortKey="Grembecka, Jolanta" sort="Grembecka, Jolanta" uniqKey="Grembecka J" first="Jolanta" last="Grembecka">Jolanta Grembecka</name><name sortKey="Kafarski, Pawel" sort="Kafarski, Pawel" uniqKey="Kafarski P" first="Pawel" last="Kafarski">Pawel Kafarski</name><name sortKey="Lowther, Jonathan" sort="Lowther, Jonathan" uniqKey="Lowther J" first="Jonathan" last="Lowther">Jonathan Lowther</name><name sortKey="Mucha, Artur" sort="Mucha, Artur" uniqKey="Mucha A" first="Artur" last="Mucha">Artur Mucha</name><name sortKey="Stack, Colin M" sort="Stack, Colin M" uniqKey="Stack C" first="Colin M." last="Stack">Colin M. Stack</name><name sortKey="Teuscher, Franka" sort="Teuscher, Franka" uniqKey="Teuscher F" first="Franka" last="Teuscher">Franka Teuscher</name><name sortKey="Trenholme, Katharine R" sort="Trenholme, Katharine R" uniqKey="Trenholme K" first="Katharine R." last="Trenholme">Katharine R. Trenholme</name></country><country name="Australie"><noRegion><name sortKey="Gardiner, Donald L" sort="Gardiner, Donald L" uniqKey="Gardiner D" first="Donald L." last="Gardiner">Donald L. Gardiner</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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