Characterization of Proplasmepsin Maturase

点击翻译按钮获取中文摘要

DESCRIPTION (provided by the applicant): Malaria is one of the world's most devastating diseases. Drug resistance is rapidly rendering our antimalarial armamentarium obsolete. The human malaria parasite Plasmodium falciparum grows by catabolizing host erythrocyte hemoglobin in its acidic food vacuole. We have shown that aspartic protease action unravels the hemoglobin molecule by strategic cleavage, exposing it for further, efficient proteolysis. Aspartic protease inhibitors that block hemoglobin degradation, kill P.falciparum parasites in culture. The parasite has four aspartic proteases called plasmepsins that participate in hemoglobin catabolism in the food vacuole. These proteases exhibit substantial functional redundancy, so ensuring blockade of plasmepsin action requires inhibition of all four. This is a difficult drug design task, to target the multiple parasite enzymes without inhibiting host aspartic proteases. Our strategy is to identify, characterize and ultimately inhibit the maturase that converts pro-plasmepsins to their active form. This will simultaneously target all the food vacuole plasmepsins and therefore the crucial process of hemoglobin degradation. The results obtained from our study should define a promising new drug target, with an eye towards future drug development.