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

Skidmore, Mark; Mohd Fadzli Mustaffa, Khairul; Cooper, Lynsay C.; Guimond, Scott E.; Yates, Edwin A.; Craig, Alister G.

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.

Citation

Skidmore, M., Mohd Fadzli Mustaffa, K., Cooper, L. C., Guimond, S. E., Yates, E. A., & Craig, A. G. (2017). A semi-synthetic glycosaminoglycan analogue inhibits and reverses Plasmodium falciparum cytoadherence. PloS one, 12(10), Article e0186276. https://doi.org/10.1371/journal.pone.0186276

• Journal Article Type: Article
• Acceptance Date: Sep 28, 2017
• Publication Date: Oct 18, 2017
• Journal: PloS one
• Print ISSN: 1932-6203
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 10
• Article Number: e0186276
• DOI: https://doi.org/10.1371/journal.pone.0186276
• Keywords: Antimalarials, Cell Adhesion, Cell Proliferation, Endothelial Cells, Erythrocytes, Glycosaminoglycans, Human Umbilical Vein Endothelial Cells, Humans, Malaria, Falciparum, Plasmodium falciparum, Protozoan Proteins
• Publisher URL: https://doi.org/10.1371/journal.pone.0186276