CYSTEINE PROTEASE INHIBITORS CURE AN EXPERIMENTAL TRYPANOSOMA-CRUZI INFECTION

Trypanosoma cruzi is the causative agent of Chagas' disease. The major protease, cruzain, is a target for the development of new chemotherap y. We report the first successful treatment of an animal model of Chag as' disease with inhibitors designed to inactivate cruzain. Treatment with fluoromethyl ketone-derivatized pseudopeptides rescued mice from lethal infection, The optimal pseudopeptide scaffold was phenylalanine -homophenylalanine. To achieve cure of infection, this pseudopeptide s caffold was incorporated in a less rode vinyl sulfone derivative. N-me thyl piperazine-Phe-homoPhe-vinyl sulfone phenyl also rescued mice fro m a lethal infection. Su; of the treated mice survived over nine month s, three without further treatment. Three mice that had entered the ch ronic stage of infection were retreated with a 20-d regimen. At the co nclusion of the experiments, five of the six mice had repeated negativ e hemacultures, indicative of parasitological cure. Studies of the eff ect of inhibitors on the intracellular amastigote form suggest that th e life cycle is interrupted because of inhibitor arrest of normal auto proteolytic cruzain processing at the level of the Golgi complex. Para sites recovered from the hearts of treated mice showed die same abnorm alities as those treated in vitro. No abnormalities were noted in the Golgi complex of host cells. This study provides proof of concept that cysteine protease inhibitors can be given at therapeutic doses to ani mals to selectively arrest a parasitic infection.