Abstract
The antimalarial activity of heparin, against which there are no resistances known, has not been therapeutically exploited due to its potent anticoagulating activity. Here, we have explored the antiplasmodial capacity of heparin-like sulfated polysaccharides from the sea cucumbers Ludwigothurea grisea and Isostichopus badionotus, from the red alga Botryocladia occidentalis, and from the marine sponge Desmapsamma anchorata. In vitro experiments demonstrated for most compounds significant inhibition of Plasmodium falciparum growth at low-anticoagulant concentrations. This activity was found to operate through inhibition of erythrocyte invasion by Plasmodium, likely mediated by a coating of the parasite similar to that observed for heparin. In vivo four-day suppressive tests showed that several of the sulfated polysaccharides improved the survival of Plasmodium yoelii-infected mice. In one animal treated with I. badionotus fucan parasitemia was reduced from 10.4% to undetectable levels, and Western blot analysis revealed the presence of antibodies against P. yoelii antigens in its plasma. The retarded invasion mediated by sulfated polysaccharides, and the ensuing prolonged exposure of Plasmodium to the immune system, can be explored for the design of new therapeutic approaches against malaria where heparin-related polysaccharides of low anticoagulating activity could play a dual role as drugs and as potentiators of immune responses.
Highlights
Previous work had demonstrated that the presence of sulfate groups was paramount for the binding of L. grisea fucosylated chondroitin sulfate (FucCS) to human lung endothelial cells and placenta cryosections under static and flow conditions[14], and that sulfated FucCS was capable of inhibiting parasitized RBC (pRBC) cytoadherence in these cell models
Because pRBC sequestration in the microvasculature of vital organs plays a key role in the pathogenesis of cerebral and pregnancy malaria, L. grisea FucCS has been proposed for the treatment of severe disease
The crucial role of sulfate groups in the context of malaria was further evidenced by the ability of L. grisea FucCS to disrupt P. falciparum rosettes, which was significantly lost upon desulfation[14]
Summary
The fast evolution of Plasmodium resistance against virtually every new drug being deployed[6], calls for urgent efforts in the research and development of new antimalarial therapeutic agents Charged polysaccharides, such as heparin, chondroitin and dextran sulfates, fucoidan, and the nonsulfated glycosaminoglycan (GAG) hyaluronan, block cytoadhesion of pRBCs to various host receptors[7,8,9,10] and disrupt P. falciparum rosettes[11,12]. Former data reporting dissociation of the anticoagulant, bleeding, and antithrombotic effects of L. grisea FucCS33, together with recent results revealing its inhibition of P. falciparum cytoadhesion and growth[14], suggest that marine sulfated glycans might offer interesting alternatives to heparin for future antimalarial therapies. To trace correlations between the structure of these new sulfated polysaccharides and their inhibition of Plasmodium growth, we have examined several compounds containing sulfated fucose units in a well-defined repetitive sequence; namely, we have determined the antimalarial and anticoagulating activities of FucCSs and sulfated fucans from the sea cucumbers L. grisea[29,34] and Isostichopus badionotus, of a sulfated galactan from the red alga Botryocladia occidentalis, and of a sulfated glycan from the marine sponge Desmapsamma anchorata
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