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Piperidones with activity against Plasmodium falciparum

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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.

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References

  • Abbruzzese A, Park MH, Folk JE (1986) Deoxyhypusine hydroxylase from rat testis. Partial purification and characterization. J Biol Chem 261:3085–3089

    PubMed  CAS  Google Scholar 

  • Abbruzzese A, Park MH, Folk JE (1988) Deoxyhypusine hydroxylase from rat testis. Partial purification and characterization. J Biol Chem 261:3085–3089

    Google Scholar 

  • Abbruzzese A, Hanauske-Abel HM, Park MH, Henke S, Folk JE (1991) The active site of deoxyhypusyl hydroxylase: use of catecholpeptides and their component chelator and peptide as molecular probes. Biochim Biophys Acta 1077:159–166

    PubMed  CAS  Google Scholar 

  • Andrus L, Szabo P, Grady RW, Hanauske A-R, Huima-Byron T, Slowinska B, Zagulska S, Hanauske-Abel HM (1998) Antiretroviral effects of deoxyhypusyl hydroxylase inhibitors. Biochem Pharmacol 55:1807–1818

    Article  PubMed  CAS  Google Scholar 

  • Ashauer-Holzgrabe U, Haller R (1986) Zur Umsetzung von N-benzylsubstituierten Piperidoncarbonsäuren mit Cer(IV)sulfat. Arch Pharm 319:1079–1083

    Article  CAS  Google Scholar 

  • Burri C, Brun R (2003) Eflornithine for the treatment of human African trypanosomiasis. Parasit Res 90:49–52

    Google Scholar 

  • Clement PM, Hanauske-Abel HM, Wolff EC, Kleinmann HK, Park MH (2002) The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro. Int J Cancer 100:491–498

    Article  PubMed  CAS  Google Scholar 

  • Csonga R, Ettmayer P, Auer M, Eckershorn C, Eder J, Klier H (1996) Evaluation of the metal ion requirement of the human deoxyhypusine hydroxylase from HeLa cells using a novel enzyme assay. FEBS Lett 380:209–214

    Article  PubMed  CAS  Google Scholar 

  • Das Gupta R, Krause-Ihle T, Bergmann B, Muller IB, Khomutov AR, Müller S, Walter RD, Luersen K (2005) 3-Aminooxy-1-aminopropane and derivatives have an antiproliferative effect on cultured Plasmodium falciparum by decreasing intracellular polyamine concentrations. Antimicrob Agents Chemother 49:2857–2864

    Article  PubMed  CAS  Google Scholar 

  • Dong Z, Arnold R, Yang Y, Park MH, Hrncirova P, Mechref Y, Novotny MV, Zhang JT (2005) Modulation of differentiation-related gene-1 expression by cell cycle blocker mimosine, revealed by proteomic analysis. Mol Cell Proteomics 4:993–1001

    Article  PubMed  CAS  Google Scholar 

  • Gimenez F, Barraud de Lagerie S, Fernandez C, Pino P, Mazier D (2003) Tumor necrosis factor alpha in the pathogenesis of cerebral malaria. Cell Mol Life Sci 8:1623–1635

    Article  CAS  Google Scholar 

  • Haider N, Eschbach ML, Dias Sde S, Gilberger TW, Walter RD, Luersen K (2005) The spermidine synthase of the malaria parasite Plasmodium falciparum: molecular and biochemical characterization of the polyamine synthesis enzyme. Mol Biochem Parasitol 142:224–236

    Article  PubMed  CAS  Google Scholar 

  • Holzgrabe U, Piening B, Kohlmorgen R, Stoll E (1988) Synthese verschieden substituierter 5-Oxo-2,6-methano-2-benzazocine. Arch Pharm 321:917–920

    Article  Google Scholar 

  • Kaiser A, Gottwald A, Wiersch C, Lindenthal B, Maier W, Seitz HM (2001) Effect of drugs inhibiting spermidine biosynthesis and metabolism on the in vitro development of Plasmodium falciparum. Parasitol Res 87:963–972

    PubMed  CAS  Google Scholar 

  • Kaiser A, Gottwald A, Maier W, Seitz HM (2003) Targeting enzymes involved in spermidine metabolism of parasitic protozoa—a possible new strategy for anti-parasitic treatment. Parasitol Res 91:508–516

    Article  PubMed  CAS  Google Scholar 

  • Kim KK, Hung LW, Yokata H, Kim R, Kim SH (1998) Crystal structures of eukaryotic translation initiation factor 5A from Methanococcus jannaschii at 1.8 Å resolution. Proc Natl Acad Sci 95:10419–10424

    Article  PubMed  CAS  Google Scholar 

  • Kwiatkowski D, Molyneux ME, Stephens S, Curtis N, Klein N, Pointaire P, Smit M, Allan R, Brewster DR, Grau GE et al (1993) Anti-TNF therapy inhibits fever in cerebral malaria. Q J Med 86:91–98

    PubMed  CAS  Google Scholar 

  • Lee YB, Folk JE (1998) Branched-chain and unsaturated 1,7-diaminoheptane derivatives as deoxyhypusine synthase inhibitors. Bioorg Med Chem 3:253–270

    Article  Google Scholar 

  • Lucas R, Juillard P, Decoster R, Redard M, Burkard D, Donati Y, Giroud C, Monso-Hinard C, De Kesel T, Buurman WA, Moore MW, Dayer JM, Fiers W, Bluethmann H, Grau GE (1997) Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria. Eur J Immunol 27:1719–1725

    Article  PubMed  CAS  Google Scholar 

  • Merz KW, Haller R (1963) Synthesen mit Pyridin-und Chinolinaldehyden. Pharm Acta Helv 38:442–456

    PubMed  CAS  Google Scholar 

  • Moloney MB, Pawluk AR, Ackland NR (1990) Plasmodium falciparum growth in deep culture. Trans R Soc Trop Med Hyg 84:516–518

    Article  PubMed  CAS  Google Scholar 

  • Molitor IM, Knobel S, Dang C, Spielmann T, Allera A, König GM (2004) Translation initiation factor eIF5A from Plasmodium falciparum. Mol Biochem Parasitol 137:65–74

    Article  PubMed  CAS  Google Scholar 

  • Moritz E, Seidensticker S, Gottwald A, Maier W, Hoerauf A, Njuguna TJ, Kaiser A (2004) The efficacy of inhibitors involved in spermidine metabolism in Plasmodium falciparum, Anopheles stephensi and Trypanosoma evansi. Parasitol Res 94:37–48

    Article  PubMed  CAS  Google Scholar 

  • Müller S, Da’dara A, Lüersen K, Wrenger C, Das Gupta R, Madhubala R, Walter RD (2000) In the human malaria parasite Plasmodium falciparum, polyamines are synthesized by a bifunctional ornithine decarboxylase, S-adenosylmethionine decarboxylase. J Biol Chem 275:8097–8102

    Article  PubMed  Google Scholar 

  • Park MH, Wolff EC (1988) Cell-free synthesis of deoxyhypusine. Separation of protein substrate and enzyme and identification of 1,3-diaminopropane as a product of spermidine cleavage. J Biol Chem 263:15264–15269

    PubMed  CAS  Google Scholar 

  • Park JH, Aravind L, Wolff EC, Kaevel J, Kim YS, Park MH (2006) Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: A HEAT-repeat-containing metalloenzyme. Proc Natl Acad Sci 103:51–56

    Article  PubMed  CAS  Google Scholar 

  • Saeftel M, Krueger A, Arriens S, Heussler V, Racz P, Fleischer B, Brombacher F, Hoerauf A (2004) Mice deficient in interleukin-4 (IL-4) or IL-4 receptor alpha have higher resistance to sporozoite infection with Plasmodium berghei (ANKA) than do naive wild-type mice. Infect Immun 72:322–331

    Article  PubMed  CAS  Google Scholar 

  • Singh S, Puri SK, Singh SK, Srivastava R, Das Gupta RC, Pandey VC (1997) Characterization of simian malarial parasite (Plasmodium knowlesi)-induced putrescine transport in rhesus monkey erythrocytes. A novel putrescine conjugate arrests in vitro growth of simian malarial parasite (Plasmodium knowlesi) and cures multidrug resistant murine malaria (Plasmodium yoelii) infection in vivo. J Biol Chem 272:13506–13511

    Article  PubMed  CAS  Google Scholar 

  • Sommer MN, Bevec D, Knebel B, Flicke B, Holscher K, Freudenreich T, Hauber I, Hauber J, Mett H (2004) Screening assay for the identification of deoxyhypusine synthase inhibitors. J Biomol Screen 5:434–438

    Article  CAS  Google Scholar 

  • Umland TC, Wolff TC, Park MH, Davies DR (2004) A new crystal structure of deoxyhypusine synthase reveals the configuration of the active enzyme and of an enzyme NAD inhibitor ternary complex. J Biol Chem 279:28697–28705

    Article  PubMed  CAS  Google Scholar 

  • Taylor CA, Senchyna M, Flanagan J, Joyce EM, Cliche DO, Boone AN, Culp-Stewart S, Thompson JE (2004) Role of eIF5A in TNF-alpha-mediated apoptosis of lamina cribrosa cells. Invest Ophthalmol Vis Sci 45:3568–3576

    Article  PubMed  Google Scholar 

  • Trager W, Williams J (1992) Extracellular (axenic) development in vitro of the erythrocytic cycle of Plasmodium falciparum. Proc Nat Acad Sci 89:5351–5355

    Article  PubMed  CAS  Google Scholar 

  • Whitworth JA, Hewitt KA (2005) Effect of malaria on HIV-1 progression and transmission. Lancet 365:1–3

    Article  Google Scholar 

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Author notes

  1. Annette Kaiser

    Present address: The German University in Cairo, Cairo, Egypt

Authors and Affiliations

  1. Institute for Medical Microbiology, Immunology and Parasitology, D-53105, Bonn, Germany

    Michael Saeftel, Ramadan Salem Sarite, Tujo Njuguna, Achim Hoerauf & Annette Kaiser

  2. Institute of Pharmacy and Food Chemistry, D-97074, Würzburg, Germany

    Ulrike Holzgrabe & Daniela Ulmer

Authors
  1. Michael Saeftel
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  2. Ramadan Salem Sarite
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  3. Tujo Njuguna
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  4. Ulrike Holzgrabe
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  5. Daniela Ulmer
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  6. Achim Hoerauf
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  7. Annette Kaiser
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Corresponding author

Correspondence to Ulrike Holzgrabe.

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Saeftel, M., Sarite, R.S., Njuguna, T. et al. Piperidones with activity against Plasmodium falciparum . Parasitol Res 99, 281–286 (2006). https://doi.org/10.1007/s00436-006-0173-4

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  • DOI: https://doi.org/10.1007/s00436-006-0173-4

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