Cysteine protease inhibitors block schistosome hemoglobin degradation in 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 of irreversible cysteine protease-specific inhibitors both arrest schistosome hemoglobin degradation in vitro. Arrest of hemoglobin degradation is followed by death of developing schistosomula 1 week later. Schistosome 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 number of eggs produced per female worm. Histopathology showed a minimal 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 identified in extracts of schistosome worms.
Department of Medicine, University of California, San Francisco 94143, USA.
M M
MM
Wasilewski
K C
KC
Lim
J
J
Phillips
J H
JH
McKerrow
D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D010450:Endopeptidases; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D007659:Ketones / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009866:Oogenesis / Q000187:drug effects*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology*; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000469:parasitology / Q000473:pathology
D015853:Cysteine Proteinase Inhibitors; D006454:Hemoglobins; D007659:Ketones; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; C534278:Ctsl protein, mouse