Inhibition of Plasmodium falciparum growth in vitro and adhesion to chondroitin-4-sulfate by the heparan sulfate mimetic PI-88 and other sulfated oligosaccharides

Abstract

A panel of sulfated oligosaccharides was tested for antimalarial activity and inhibition of adhesion to the placental malaria receptor chondroitin-4-sulfate (CSA). The heparan sulfate mimetic PI-88, currently undergoing phase II anticancer trials, displayed the greatest in vitro antimalarial activity against Plasmodium falciparum (50% inhibitory concentration of 7.4 microM) and demonstrated modest adhesion inhibition to cell surface CSA.

FIG. 1.

Stage-specific effects of PI-88 on in vitro development of P. falciparum IEs. P. falciparum Dd2 IEs were treated with either 100 μg/ml (gray bars) or 50 μg/ml (striped bars) PI-88 or left untreated (black bars) starting at either ring stage (A, 26-h treatment) or trophozoite stage (B, 19-h treatment). Percent parasitemia was determined by microscopic examination of Giemsa-stained thin smears. Representative experiments are shown.

FIG. 2.

Effect of PI-88 on CSA- and CD36-specific adhesion of P. falciparum IEs. CSA-binding (3D7 selected on CHO-K1 cells [3D7^csa]) or CD36-binding (unselected 3D7) P. falciparum IEs were preincubated with various concentrations of PI-88 prior to adhesion to CHO-K1 (black bars) or C32 (gray bars) cells, respectively. CSA-specific adhesion was determined by the addition of 100 μg/ml soluble CSA, whereas CD36-specific adhesion was determined using 5 μg/ml of the anti-CD36 monoclonal antibody FA6/152. The average percentages of binding (±standard deviations) compared to that for untreated controls for three independent experiments are shown.