Plasmodium falciparum Plasmepsins IX and X: Structure- Function Analysis and the Discovery of New Lead Antimalarial drugs

Abstract

Malaria is a deadly parasitic infection that poses an enormous threat to global health. While drugs are available, all of our current antimalarials are being gradually rendered ineffective by spreading drug resistance. Reports of increasing tolerance to artemisinin combination therapies, our most potent antimalarial treatments, are particularly concerning. To combat this problem there is an urgent need to identify new and unique targets within the malaria parasite against which novel chemotherapeutics can be developed. Studies investigating the antimalarial activity of HIV protease inhibitors (HIV PIs) have shown that these drugs can inhibit the growth of Plasmodium in vitro, in vivo and ex vivo at clinically relevant concentrations. While the anti-parasitic action of these drugs is not fully understood, it is believed these agents inhibit the growth of parasites by targeting an essential malarial aspartic protease or plasmepsin (PM) and that these enzymes may represent new targets for drug development. The aim of this thesis was to investigate the Plasmodium falciparum aspartic proteases PM IX and X as potential new targets for antimalarial development.