CENTRAL ROLE OF HEMOGLOBIN DEGRADATION IN MECHANISMS OF ACTION OF 4-AMINOQUINOLINES, QUINOLINE METHANOLS, AND PHENANTHRENE METHANOLS

We have used a specific inhibitor of the malarial aspartic proteinase plasmepsin I and a nonspecific cysteine proteinase inhibitor to invest igate the importance of hemoglobin degradation in the mechanism of act ion of chloroquine, amodiaquine, quinine, mefloquine (MQ), halofantrin e, and primaquine. Both proteinase inhibitors antagonized the antipara sitic activity of all drugs tested with the exception of primaquine. A n inhibitor of plasmepsin I, Ro40-4388, reduced the incorporation of r adiolabelled chloroquine and quinine into malarial pigment by 95%, whi le causing a 70% reduction in the incorporation of radiolabelled MQ. C ysteine proteinase inhibitor E64 reduced the incorporation of chloroqu ine and quinine into malarial pigment by 60 and 40%, respectively. Thi s study provides definitive support for the central role of hemoglobin degradation in the mechanism of action of the 4-aminoquinolines and t he quinoline and phenanthrene methanol antimalarials.