CYSTEINE PROTEASE INHIBITORS BLOCK SCHISTOSOME HEMOGLOBIN DEGRADATIONIN-VITRO AND DECREASE WORM BURDEN AND EGG-PRODUCTION IN-VIVO

Schistosome parasites utilize hemoglobin as a major protein source for their metabolism. Degradation of hemoglobin has been hypothesized to be mediated by both cysteine and aspartyl proteases secreted into the lumen of the parasite intestine. We now show that two distinct types o f irreversible cysteine protease-specific inhibitors both arrest schis tosome hemoglobin degradation in vitro. Arrest of hemoglobin degradati on is followed by death of developing schistosomula 1 week later. Schi stosome infected mice treated by a dose of 2 mg inhibitor per day for 1 week early in infection, and 2 weeks at the time of egg production, showed a significant reduction in worm burden, hepatomegaly, and the n umber of eggs produced per female worm. Histopathology showed a minima l immune response to those eggs which were produced, consistent with a delay in egg production relative to untreated infections. By tagging the inhibitor with biotin, specific cysteine protease targets were ide ntified in extracts of schistosome worms.