We have completed a set of in vivo studies using a mouse model of Chagas disease treated by intraperitoneal or oral administration of the vinyl sulfone analogues. Previous studies had shown that these cysteine protease inhibitors will rescue mice from a lethal infection of T. cruzi. These studies now show that i.p. doses of 2 mg inhibitor per day for 20 days are sufficient to cure mice of T. cruzi. Furthermore, we established a model of chronic T. cruzi infection, and also showed that this can be parasitologically cured with the same dose of inhibitor. These studies now provide proof of concept that cysteine protease inhibitors can rescue mice from a lethal infection of T. cruzi, cure mice following a lethal acute or chronic established infection, and have efficacy by both intraperitoneal and oral dosing. A new arm of our project is directed at developing inhibitors for the malaria cysteine protease, falcipain, known to be involved in the function of the Plasmodium food vacuole for hemoglobin degradation. Inhibitors block in vitro replication of P. falciparum, including chloroquine-resistant strains, and cures of mice infected with murine malaria have also been demonstrated with several of our pseudopeptide analogues. The target enzyme has been identified, and current efforts are underway to produce sufficient recombinant enzyme for crystallographic studies and further analysis along the lines that we followed for the T. cruzi target. The Computer Graphics Laboratory resources are used for molecular modelling.
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