Identification of Phosphinate Dipeptide Analog Inhibitors Directed against the Plasmodium falciparum M17 Leucine Aminopeptidase as Lead Antimalarial Compounds

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：6024 - 6031
• 全文大小：244K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

Previous studies have pinpointed the M17 leucyl aminopeptidase of Plasmodium falciparum (PfLAP) as atarget for the development of new antimalarials. This metallo-exopeptidase functions in the terminal stagesof hemoglobin digestion and is inhibited by bestatin, a natural analog of Phe-Leu. By screening novelphosphinate dipeptide analogues for inhibitory activity against recombinant PfLAP, we have discoveredtwo 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 ofPfLAP. Both compounds inhibit the growth of P. falciparum in vitro, exhibiting IC₅₀ values against thechloroquine-resistant clone Dd2 of 20-40 and 12-23 M, respectively. While bestatin exhibited some invivo activity against Plasmodium chabaudi chabaudi, compound 4 reduced parasite burden by 92%. Thesestudies establish the PfLAP as a prime target for the development of antimalarial drugs and provide importantnew lead compounds.