Proteases as Drug Targets for the Treatment of Malaria

Abstract

This chapter discusses proteases as drug targets for the treatment of malaria. To overcome parasite resistance and to produce new generations of antimalarial drugs, parasite proteinases have been identified as important new targets in the process of hemoglobin degradation and parasite nutrition. The chapter discusses the role of one cysteine proteinase, two aspartic proteinases, and an aminopeptidase in this catabolic process. A proplasmepsin processing proteinase appears to be critical for the activation of plasmepsin I and is thus a further potential drug target. Furthermore, the chapter turns to the discussion of cysteine proteinase, falcipain, and the aspartic proteinases, plasmepsins I and II, which have been studied in detail till now. Substrate specificities have been determined, X-ray structures or models have been produced, and several series of inhibitors of the enzymes have been tested. For the future, more screening for new lead inhibitors will be necessary and these new compounds, along with those already identified, must be modified and adapted for therapeutic use. Proteases are excellent drug targets in Plasmodium and represent the Achilles heel of these parasites.