Plasmepsins as potential targets for new antimalarial therapy

Abstract

Malaria is one of the major diseases in the world. Due to the rapid spread of parasite resistance to available antimalarial drugs there is an urgent need for new antimalarials with novel mechanisms of action. Several promising targets for drug intervention have been revealed in recent years. This review addresses the parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the hemoglobin catabolism that occurs during the erythrocytic stage of the malarial parasite life cycle. Four Plasmodium species are responsible for human malaria; P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on inhibitors of the haemoglobin-degrading plasmepsins of the most lethal species, P. falciparum; Plm I, Plm II, Plm IV, and histo-aspartic protease (HAP). Previously, Plm II has attracted the most attention. With the identification and characterization of new plasmepsins and the results from recent plasmepsin knockout studies, it now seems clear that in order to achieve high-antiparasitic activities in P. falciparum-infected erythrocytes it is necessary to inhibit several of the haemoglobin-degrading plasmepsins. Herein we summarize the structure-activity relationships of the Plm I, II, IV, and HAP inhibitors. These inhibitors represent all classes which, to the best of our knowledge, have been disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin II complexes available in the protein data bank are briefly discussed and compared.

Caracterización parcial del proteoma del trofozoito de Plasmodium falciparum bajo tratamiento con quinina, mefloquina y el antiplasmodial natural diosgenona

“…Plasmepsin III is one of the 10 plasmepsins coded in the P. falciparum genome and the protein is located in the food vacuole. Thus, it has been proposed as a potential anti-malarial therapeutic target (32). Upregulation of this protein by mefloquine suggests increased hemoglobin degradation, which agrees with the known mode of action of the drug.…”

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

“…Individual data points are shown by crosses. Numbering of inhibitors is as in [3]. Note that the numbers of the known inhibitors are not in boldface to distinguish them from those discovered in this study.…”

“…Inhibitors of PMs are fatal to the parasites [3], which indicates that PMs are relevant drug targets (see Ref [3] for a comprehensive list of known PM II inhibitors). Furthermore, several small-molecule inhibitors of retroviral and human aspartic proteases, namely HIV-protease [4] and renin [5], are effective and safe medicines, which provides additional support to the relevance of PMs as drug targets.…”

Anti-malaria drug development targeting the M1 alanyl and M17 leucyl aminopeptidases

“…13,18,19 However, knockout experiments have shown that the DV plasmepsins and falcipains 2 and 2′ are individually not essential to parasite survival, and because of this redundancy between the function of these enzyme classes it has proved difficult to develop drugs that effectively block the digestive process within the DV. [21][22][23][24] Peptides produced in the DV may be further processed to dipeptides by a dipeptidyl aminopeptidase I, an orthologue of mammalian cathepsin C. 25,26 Small peptides and dipeptides may also be reduced to free aminoacids within the DV and/or transported to the parasite cytosol for processing by aminopeptidases. 20,[27][28][29][30][31][32][33] Aminopeptidases are essential in releasing aminoacids from haemoglobin-derived peptides and are thus central to the growth and development of malaria parasites in the erythrocyte.…”