ANTIMALARIAL SYNERGY OF CYSTEINE AND ASPARTIC PROTEASE INHIBITORS

It has been proposed that the Plasmodium falciparum cysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act co operatively to hydrolyze hemoglobin as a source of amino acids for ery throcytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When inc ubated with cultured P. falciparum parasites, cysteine and aspartic pr otease inhibitors exhibited synergistic effects in blocking parasite m etabolism and development. The inhibitors also demonstrated apparent s ynergistic inhibition of plasmodial hemoglobin degradation both in cul ture and in a murine malaria model. When evaluated for the treatment o f murine malaria, a combination of cysteine and aspartic protease inhi bitors was much more effective than higher concentrations of either co mpound used alone, These results support a model whereby plasmodial cy steine and aspartic proteases participate in the degradation of hemogl obin, and they suggest that combination antimalarial therapy with inhi bitors of the two classes of proteases is worthy of further study.