Piperidones with activity against Plasmodium falciparum
- 21 March 2006
- journal article
- Published by Springer Science and Business Media LLC in Zeitschrift für Parasitenkunde
- Vol. 99 (3), 281-286
- https://doi.org/10.1007/s00436-006-0173-4
Abstract
The increasing resistance of the malaria parasites has enforced new strategies of finding new drug targets. We have isolated two genes involved in spermidine metabolism, encoding deoxyhypusine synthase (DHS) and eukaryotic initiation factor 5A (eIF-5A) in the malaria parasites. eIF-5A is activated by the formation of the unusual amino acid hypusine. This process occurs in two steps. DHS transfers an aminobutyl moiety from the triamine spermidine to a specific lysine residue in the eIF-5A precursor protein to form deoxyhypusine. In a second step, deoxyhypusine hydroxylase (DHH), completes hypusine biosynthesis. We used DHH inhibitors, being effective in mammalian cells, to study an antiplasmodicidal effect in Plasmodium falciparum. Experiments with the antifungal drug ciclopiroxolamine, an α-hydroxypyridone, and the plant amino acid l-mimosine, a 4-pyridone, resulted in an antiplasmodial effect in vitro. Using mimosine as a lead structure, alkyl 4-oxo-piperidine 3-carboxylates were found to have the most efficient antiplasmodial effects in vitro and in vivo.Keywords
This publication has 33 references indexed in Scilit:
- Modulation of Differentiation-related Gene 1 Expression by Cell Cycle Blocker Mimosine, Revealed by Proteomic AnalysisMolecular & Cellular Proteomics, 2005
- Effect of malaria on HIV-1 progression and transmissionThe Lancet, 2005
- Role of eIF5A in TNF-α–Mediated Apoptosis of Lamina Cribrosa CellsPublished by Association for Research in Vision and Ophthalmology (ARVO) ,2004
- Screening Assay for the Identification of Deoxyhypusine Synthase InhibitorsSLAS Discovery, 2004
- The efficacy of inhibitors involved in spermidine metabolism in Plasmodium falciparum, Anopheles stephensi and Trypanosoma evansiZeitschrift für Parasitenkunde, 2004
- The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitroInternational Journal of Cancer, 2002
- Evaluation of the metal ion requirement of the human deoxyhypusine hydroxylase from HeLa cells using a novel enzyme assayFEBS Letters, 1996
- The active site of deoxyhypusyl hydroxylase: use of catecholpeptides and their component chelator and peptide moieties as molecular probesBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1991
- Cer(IV)oxidationen von β-Aminoketonen. 5. Mitt. Synthese verschieden substituierter 5-Oxo-2,6-methano-2-benzazocineArchiv der Pharmazie, 1988
- Zur Umsetzung von N-benzylsubstituierten Piperidoncarbonsäureestern mit Cer(IV)-sulfatArchiv der Pharmazie, 1986