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.

doi:10.1128/AAC.00709-17

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.

Authors

Michelle J. Boyle

Mark Skidmore m.a.skidmore@keele.ac.uk

Benjamin Dickerman

Lynsay Cooper

Anthony Devlin

Edwin Yates

Paul Horrocks p.d.horrocks@keele.ac.uk

Craig Freeman

Wengang Chai

James G. Beeson

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.

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
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
Publisher URL	https://doi.org/10.1128/aac.00709-17