Malaria is a severe health burden, threatening nearly half the global population. Current antimalarial medicines are failing due to increasing parasite resistance, driving a need for new therapeutics with novel targets. Plasmodium parasites are obligate intracellular pathogens, their survival and pathogenicity being contingent on successful egress of daughter parasites from host erythrocytes and subsequent invasion of new erythrocytes. Novel antimalarials that block egress or invasion could therefore be highly effective at arresting infection.
Parasites have four protein disulphide isomerases (PDIs) that are likely involved in folding proteins required for egress and invasion, potentially representing novel drug targets. In other eukaryotes, PDIs are established protein folding chaperones and disulphide bonding mediators in the endoplasmic reticulum.
We have shown that mammalian PDI inhibitors and their chemical analogues impede Plasmodium falciparum egress and invasion by appearing to cause the misfolding of at least two proteins which are important for these parasite-specific processes. We have developed a novel inhibitor that is highly specific for parasite PDIs with demonstrated potency against invasion, egress, and growth of asexual blood-stage P. falciparum. This compound also killed another clinically relevant Plasmodium species, suggesting that the inhibitor could be effective against multiple species that infect humans.
We also investigated the biological functions of PfPDIs by tagging their genes with a genetic knockdown switch. Fluorescent microscopy of two PDI-tagged parasite lines confirmed PfPDI-Trans and PfPDI-14 are localised in the endoplasmic reticulum as anticipated. Through associated functional assays, PfPDI-Trans was implicated in post-translational folding of merozoite surface protein 1, linking this PfPDI to a role in parasite egress. With a now established a relationship between PfPDIs and the essential processes of egress and invasion, repurposing existing mammalian PDI inhibitors to versions highly specific for only the parasite machinery offers a novel means of eliminating malaria parasites.