A semi-synthetic glycosaminoglycan analogue inhibits and reverses Plasmodium falciparum cytoadherence

PLoS One. 2017 Oct 18;12(10):e0186276. doi: 10.1371/journal.pone.0186276. eCollection 2017.

Abstract

A feature of mature Plasmodium falciparum parasitized red blood cells is their ability to bind surface molecules of the microvascular endothelium via the parasite-derived surface protein Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). This ligand is associated with the cytoadherence pathology observed in severe malaria. As pRBC treated with effective anti-malarial drugs are still able to cytoadhere, there is therefore a need to find an adjunct treatment that can inhibit and reverse the adhesion process. One semi-synthetic, sulfated polysaccharide has been identified that is capable of inhibiting and reversing sequestration of pRBC on endothelial cells in vitro under physiological flow conditions. Furthermore, it exhibits low toxicity in the intrinsic (APTT assay) and extrinsic (PT assay) clotting pathways, as well as exhibiting minimal effects on cell (HUVEC) viability (MTT proliferation assay). These findings suggest that carbohydrate-based anti-adhesive candidates may provide potential leads for therapeutics for severe malaria.

MeSH terms

  • Antimalarials / administration & dosage*
  • Antimalarials / chemical synthesis
  • Cell Adhesion / drug effects*
  • Cell Proliferation / drug effects
  • Endothelial Cells / drug effects
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Erythrocytes / pathology
  • Glycosaminoglycans / administration & dosage*
  • Glycosaminoglycans / adverse effects
  • Glycosaminoglycans / chemical synthesis
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / parasitology
  • Malaria, Falciparum / pathology
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / pathogenicity
  • Protozoan Proteins / metabolism

Substances

  • Antimalarials
  • Glycosaminoglycans
  • Protozoan Proteins
  • erythrocyte membrane protein 1, Plasmodium falciparum