Marques J et al. (2016), Marine organism sulfated polysaccharides exhibi...

ECB-ART-44623

Sci Rep 2016 Apr 13;6:24368. doi: 10.1038/srep24368.

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Marine organism sulfated polysaccharides exhibiting significant antimalarial activity and inhibition of red blood cell invasion by Plasmodium.

Marques J , Vilanova E , Mourão PA , Fernàndez-Busquets X .

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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.

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Genes referenced: LOC100887844 LOC115919910

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	Figure 1. Chemical structures of the sulfated polysaccharides used in this work.(a) The L. grisea and I. badionotus fucosylated chondroitin sulfates share a similar backbone (left) but differ on their sulfated fucose branches (right). (b) L. grisea and I. badionotus sulfated fucans have similar tetrasaccharide repeating structures but differ exclusively on the sulfation of the second unit. (c) The sulfated galactan from the red alga B. occidentalis contains alternating α- and β-galactose units with distinct sulfation patterns. Sulfation sites are shadowed.
	Figure 2. Alcian Blue-stained polyacrylamide gel electrophoresis analysis of sulfated polysaccharides.Approximate molecular masses were confirmed by size exclusion chromatography. CSA: chondroitin sulfate A.
	Figure 3. In vitro analysis of antimalarial and anticoagulating activities of sulfated polysaccharides.(a) Growth inhibition assays of P. falciparum cultures. (b) Activated partial thromboplastin time assay of anticoagulant activities, expressed as the ratio between clotting times in the presence (T1) and absence (T0) of polysaccharides. Percentages represent the respective anticlotting activities relative to that of heparin. CSA is used as a negative control for its lack of anticoagulating activity. The results are shown as the means of three independent experiments; the error bars represent standard deviations.
	Figure 4. Microscopic images of Giemsa-stained in vitro pRBC cultures of P. falciparum treated with sulfated polysaccharides in an invasion inhibition assay.Pictures corresponding to the cycle phases when rings and trophozoites+schizonts are the dominant forms expected were taken, respectively, 20 and 40 h after treatment. Arrows and arrowheads indicate examples, respectively, of ring stages and of merozoites that have failed to invade pRBCs.

	Figure 6. Cytotoxicity and in vivo antimalarial activity analyses of sulfated polysaccharides.(a) Unspecific toxicity for human umbilical vein endothelial cell cultures of sulfated polysaccharides assayed at concentrations around their respective IC50 for P. falciparum growth in vitro. The results are shown as the means of three independent experiments; the error bars represent standard deviations. (b) Kaplan-Meier plot for the in vivo assay of the effect on P. yoelii-infected mice (n = 5 animals/sample) of polysaccharides administered iv at the estimated μg mL−1 day−1 indicated in Table 3. Chloroquine was administered iv as a positive control at a dose of 5 mg kg−1 day−1. (c) Western blot for the detection of IgGs against P. yoelii antigens in the serum of surviving infected mice that had been treated 35 days before with chloroquine or with the I. badionotus fucan. The untreated control corresponds to a noninfected mouse of the same age. (d,e) Microscope images of blood samples from the surviving I. badionotus fucan-treated mouse at (d) day 4 and (e) day 40 after reinfection without further treatment.

References [+] :

, Severe and complicated malaria. World Health Organization Malaria Action Programme. 1986, Pubmed