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

Tina S. Skinner-Adams, Jonathan Lowther, Franka Teuscher, Colin M. Stack, Jolanta Grembecka, Artur Mucha, Pawel Kafarski, Katharine R. Trenholme, John P. Dalton, Donald L. Gardiner

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    87 Citations (Scopus)

    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.
    Original languageEnglish
    Number of pages8
    JournalJournal of Medicinal Chemistry
    DOIs
    Publication statusPublished - 2007

    Keywords

    • Plasmodium falciparum
    • antimalarials
    • bestatin
    • malaria
    • research
    • treatment

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