Identification of heparin modifications and polysaccharide inhibitors of Plasmodium falciparum merozoite invasion that have potential for novel drug development.

Boyle, Michelle J.; Skidmore, Mark; Dickerman, Benjamin; Cooper, Lynsay; Devlin, Anthony; Yates, Edwin; Horrocks, Paul; Freeman, Craig; Chai, Wengang; Beeson, James G.

Abstract

Despite recent successful control efforts, malaria remains a leading global health burden. Alarmingly, resistance to current antimalarials is increasing, and the development of new drug families is needed to maintain malaria control. Current antimalarials target the intra-erythrocytic developmental stage of the Plasmodium falciparum life cycle. However, the invasive extracellular parasite form, the merozoite, is also an attractive target for drug development. We have previously demonstrated that heparin-like-molecules, including those with low molecular weights and low anti-coagulant activities are potent and specific inhibitors of merozoite invasion and blood-stage replication. Here we tested a large panel of heparin-like-molecules and sulfated polysaccharides together with various modified chemical forms for inhibitory activity against P. falciparum merozoite invasion. We identified chemical modifications that improve inhibitory activity and identified several additional sulfated polysaccharides with strong inhibitory activity. These studies have important implications for the further development of heparin-like-molecules as anti-malarial drugs, and for understanding merozoite invasion.

Citation

Boyle, M. J., Skidmore, M., Dickerman, B., Cooper, L., Devlin, A., Yates, E., Horrocks, P., Freeman, C., Chai, W., & Beeson, J. G. (2017). Identification of heparin modifications and polysaccharide inhibitors of Plasmodium falciparum merozoite invasion that have potential for novel drug development. Antimicrobial Agents and Chemotherapy, 61(11), https://doi.org/10.1128/AAC.00709-17

• Journal Article Type: Article
• Acceptance Date: Sep 11, 2017
• Online Publication Date: Oct 24, 2017
• Publication Date: Sep 11, 2017
• Journal: Antimicrobial Agents and Chemotherapy
• Print ISSN: 0066-4804
• Electronic ISSN: 1098-6596
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 61
• Issue: 11
• DOI: https://doi.org/10.1128/AAC.00709-17
• Keywords: heparin; drug development
• Public URL: https://keele-repository.worktribe.com/output/409493
• Publisher URL: https://doi.org/10.1128/aac.00709-17