Iron chelators: mode of action as antimalarials.

Abstract:

:Malaria parasites growing inside human erythrocytes differ from mammalian cells in their mode of acquisition of bioavailable iron and in their susceptibility to the antiproliferative action of iron chelators. We have assessed here three major properties associated with these phenomena: (a) the stage-dependent nature of parasite iron mobilization from the host and its integration into parasite proteins; (b) the differential permeability of the plasma membrane to iron chelators, and (c) the in situ generation of toxic chelator-metal complexes in the intracellular milieu of infected cells. We have used a combination of synthetic and natural iron chelators with similar iron-binding properties but markedly different capacities to permeate membranes. The profiles of action of these agents on the in vitro growth of Plasmodium falciparum were assessed in terms of inhibitory concentrations, speed of action, stage dependence and reversibility of effects. These profiles provided the basis for a working model of chelator action on parasitized cells. The model allowed us to predict major improvements in the antimalarial performance of iron chelators when used in appropriate combinations of slow-and fast-permeating substances. The synergistic actions found in vitro for various combinations of iron chelators are in accordance with the model and have implications for the design of therapeutic schemes.

journal_name

Acta Haematol

journal_title

Acta haematologica

authors

Cabantchik ZI,Glickstein H,Golenser J,Loyevsky M,Tsafack A

doi

10.1159/000203952

subject

Has Abstract

pub_date

1996-01-01 00:00:00

pages

70-7

issue

1

eissn

0001-5792

issn

1421-9662

journal_volume

95

pub_type

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