Malaria is a devastating disease caused by the Plasmodium parasite. Due to the threat of emerging drug resistance, the current arsenal of clinically used artemisinin combination therapies and drug candidates undergoing clinical assessment may not be sufficient in eliminating the disease. Thus, novel chemotypes that target multiple stages of the parasite lifecycle are required to continually populate the antimalarial clinical portfolio.
The P. falciparum parasite expresses ten cathepsin D-like or A1 family aspartyl proteases, known as plasmepsins. The plasmepsins have diverse roles across the parasite’s lifecycle and several are essential for parasite development. Plasmepsin 5 is required for licensing parasite proteins for export to the host erythrocyte. Plasmepsin 9 has an indispensable role in invasion, while plasmepsin 10 is vital for both invasion and egress from the host erythrocyte. Plasmepsin 5, 9 and 10 are each considered attractive antimalarial drug targets.
This presentation will summarise our past and ongoing research on the optimisation of peptidomimetic inhibitors used to pharmacologically validate the role of plasmepsin 5 in protein export and parasite survival. The second part of the presentation will focus on the development of peptidomimetic inhibitor of PM10 with potent antimalarial activity.