The antimalarial action of desferal involves a direct access route to erythrocytic (Plasmodium falciparum) parasites

Mark Loyevsky, Simon D. Lytton, Brenda Mester, Jacqueline Libman, Abraham Shanzer, Z. Ioav Cabantchik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

We designed the N-methylanthranilic-desferrioxamine (MA-DFO) as a fluorescent iron (III) chelator with improved membrane permeation properties. Upon binding of iron (III), MA-DFO fluorescence is quenched, thus allowing traceability of drug-iron (III) interactions. MA-DFO is well tolerated by mammalian cells in culture. Its antimalarial activity is pronounced: IC50 values on in vitro (24-h) growth of Plasmodium falciparum were 3±1 μM for MA-DFO compared with 30±8 for DFO. The onset of growth inhibition of rings or trophozoites occurs 2-4 h after exposure to 13 μM MA-DFO. This effect is commensurate with MA-DFO permeation into infected cells. In a 24-h exposure to MA-DFO or DFO, trophozoites take up either compound to ∼ 10% of the external concentration, rings to 5%, and noninfected cells to < 1%. Red cells encapsulated with millimolar concentrations of DFO or MA-DFO fully support parasite invasion and growth. We conclude that extracellular MA-DFO and DFO gain selective access into parasites by bypassing the host. The rate-limiting step is permeation through the parasite membrane, which MA-DFO accomplishes faster than DFO, in accordance with its higher hydrophobicity. These views are consistent with the proposed duct, which apparently provides parasitized cells with a window to the external medium.

Original languageEnglish
Pages (from-to)218-224
Number of pages7
JournalJournal of Clinical Investigation
Volume91
Issue number1
StatePublished - Jan 1993

Keywords

  • Antimalarial
  • Chelators
  • Chemotherapy
  • Drug delivery
  • Erythocyte
  • Fluorescence
  • Iron
  • Malaria
  • Permeability
  • Plasmodium falciparum

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