Inhibitors of Plasmepsin II—potential antimalarial agents

In order to overcome the problem of drug resistance in malaria, it appears wise to concentrate drug discovery efforts toward new structural classes and new mechanisms of action. We report our results, targeting Plasmepsin II, a Plasmodium falciparum aspartic protease active in hemoglobin degradation, a parasite specific catabolic pathway. The results show that the new structural class is not only inhibiting PMII in vitro but is also active in a P. falciparum infected human red blood cell assay.

Graphical abstractOptimization of a lead compound which showed low nanomolar activity on the isolated enzyme Plasmepsin II but above micromolar activity on a cell-based assay using Plasmodium falciparum infected human red blood cells allowed the discovery of compounds with submicromolar activity in the whole cell-based assay and without assay to assay shift.Figure optionsDownload full-size imageDownload as PowerPoint slide