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Abstract

The asexual erythrocytic stage of Plasmodium falciparum was grown in culture in the presence or absence of glycoconjugate polyanions of varying structure, size and substitutions. Heparin, dextran sulfate, fucoidan and pentosan polysulfate had antimalarial IC50 values between one and 11 microg ml(-1). Constituent heparin disaccharides were ineffective against the malaria parasite and desulfation from either the O- or N-substitution sites of heparin or reduction of the uronic acid carboxyl group neutralized the antimalarial response to varying degrees. Immobilization of heparin onto agarose beads still permitted antimalarial activity suggesting that parasite uptake of the glycoconjugate is not required for inhibition. Accordingly, it is concluded that invasion of free parasites into the erythrocytes was inhibited rather than parasite maturation within the red cell. Merozoite surface antigen-1 was apparently prevented from binding to human erythrocytes in the presence of highly sulfated polyanions and, in a dose-dependent fashion, heparin.

Plasmodium falciparum BAEBL Binds to Heparan Sulfate Proteoglycans on the Human Erythrocyte Surface

“…8C). The addition of high concentrations of heparin (2.33-233 g/ml) potently inhibited merozoite invasion, as previously reported (7,38). However, low concentrations of heparin (Յ1.17 g/ml) enhanced merozoite invasion.…”

“…Our results showing the binding inhibition of BAEBL by heparin are not sufficient to explain the almost complete inhibition of the merozoite invasion by heparin because BAEBL is not an essential ligand for the invasion (18). The binding of full-length MSP-1 (merozoite surface protein-1), which is bound to erythrocytes in a sialic acid-dependent manner, was suggested to be inhibited by the addition of saccharide anions, including heparin (7). In addition, bindings of PfRH5 (P. falciparum reticulocyte-binding homologue 5) and EBA-175 to erythrocytes were also reported to be inhibited by the addition of heparin (49).…”

“…Several studies have already reported that heparin and other sulfated glycoconjugates inhibit the growth of malarial parasites (7)(8)(9)11). In addition, some sulfated chemical compounds inhibit parasite entry into erythrocytes (6,10).…”

“…Here we observed the same result with BAEBL, which suggests the possibility that binding inhibition of multiple ligands, including, at least, BAEBL, MSP1, EBA-175, and PfRH5, by heparin results in invasion inhibition. One potential mechanism for this inhibition, as proposed by Clark et al (7), is that the saccharide anions, such as heparin, effectively mimic the anionic character of the erythrocyte surface receptor, thereby competitively inhibiting MSP-1 binding to erythrocytes. Our findings that soluble heparin inhibited both sialic acid-and HSdependent bindings of BAEBL by the blockage of some critical motifs support the notion of competitive binding inhibition.…”

Fucosylated Chondroitin Sulfate Inhibits Plasmodium falciparum Cytoadhesion and Merozoite Invasion

“…Recently, a pivotal role for cytoadherence through the endothelial protein C receptor in the development of severe malaria was described (30). Cytoadhesion of Pf-iEs is mediated by members of the P. falciparum membrane protein 1 (PfEMP-1) family, which mediates parasite interactions with various host receptors, including CD36 (31), intercellular adhesion molecule 1 (ICAM-1) (32), and chondroitin sulfate A (CSA) (33,34), a receptor frequently associated with MiP (15,33,35) Glycosaminoglycans (GAGs), including heparin, have been employed as a strategy to prevent malaria complications due to their abilities to inhibit parasite cytoadhesion, to block invasion, and to disrupt rosettes (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). However, the side effects of heparin, mostly serious bleeding (47), and the potential risk of contamination (because some GAGs are obtained from mammals) have hampered GAG-based adjunct therapies.…”