Plasmodium spp. parasites that cause malaria disease remain a significant global-health burden. With the spread of parasites resistant to artemisinin combination therapies in Southeast Asia, there is a growing need to develop new antimalarials with novel targets. Invasion of the red blood cell by Plasmodium merozoites is essential for parasite survival and proliferation, thus representing an attractive target for therapeutic development. Red blood cell invasion requires a co-ordinated series of protein/protein interactions, protease cleavage events, intracellular signals, organelle release and engagement of an actin-myosin motor, which provide many potential targets for drug development. As these steps occur in the bloodstream, they are directly susceptible and exposed to drugs. A number of invasion inhibitors against a diverse range of parasite proteins involved in these different processes of invasion have been identified, with several showing potential to be optimised for improved drug-like properties. In this review, we discuss red blood cell invasion as a drug target and highlight a number of approaches for developing antimalarials with invasion inhibitory activity to use in future combination therapies.
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DW received funding from the NHMRC (Fellowship APP1035715, Project Grant APP1143974) and
University of Adelaide Beacon Fellowship. MJB received funding from NHMRC (Career
Development Fellowship APP1141632 and Project Grant APP112656), and JGB (1077636) and
T.dKW (1136300) were supported by NHMRC Senior Research Fellowships. JGB is a member of
the NHMRC Australian Centre for Research Excellence in Malaria Elimination.