Genetic and chemical validation of <i>Plasmodium falciparum</i> aminopeptidase <i>Pf</i>A-M17 as a drug target in the hemoglobin digestion pathway.

Abstract

<i>Plasmodium falciparum,</i> the causative agent of malaria, remains a global health threat as parasites continue to develop resistance to antimalarial drugs used throughout the world. Accordingly, drugs with novel modes of action are desperately required to combat malaria. <i>P. falciparum</i> parasites infect human red blood cells where they digest the host's main protein constituent, hemoglobin. Leucine aminopeptidase <i>Pf</i>A-M17 is one of several aminopeptidases that have been implicated in the last step of this digestive pathway. Here, we use both reverse genetics and a compound specifically designed to inhibit the activity of <i>Pf</i>A-M17 to show that <i>Pf</i>A-M17 is essential for <i>P. falciparum</i> survival as it provides parasites with free amino acids for growth, many of which are highly likely to originate from hemoglobin. We further show that loss of <i>Pf</i>A-M17 results in parasites exhibiting multiple digestive vacuoles at the trophozoite stage. In contrast to other hemoglobin-degrading proteases that have overlapping redundant functions, we validate <i>Pf</i>A-M17 as a potential novel drug target.