THE ANTIMALARIAL ACTION OF DESFERAL INVOLVES A DIRECT ACCESS ROUTE TO ERYTHROCYTIC (PLASMODIUM-FALCIPARUM) PARASITES

被引:97
作者
LOYEVSKY, M
LYTTON, SD
MESTER, B
LIBMAN, J
SHANZER, A
CABANTCHIK, ZI
机构
[1] HEBREW UNIV JERUSALEM,DEPT BIOL CHEM,IL-91904 JERUSALEM,ISRAEL
[2] WEIZMANN INST SCI,DEPT ORGAN CHEM,IL-76100 REHOVOT,ISRAEL
关键词
ERYTHOCYTE; PERMEABILITY; DRUG DELIVERY; MALARIA; PLASMODIUM-FALCIPARUM; IRON; ANTIMALARIAL; CHELATORS; CHEMOTHERAPY; FLUORESCENCE;
D O I
10.1172/JCI116174
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 muM 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 muM 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 approximately 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.
引用
收藏
页码:218 / 224
页数:7
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