Trypanosoma cruzi is the causative agent of
Chagas' disease. The major
protease,
cruzain, is a target for the development of new
chemotherapy. We report the first successful treatment of an animal model of
Chagas' 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 scaffold was incorporated in a less toxic
vinyl sulfone derivative. N-methyl
piperazine-Phe-homoPhe-
vinyl sulfone phenyl also rescued mice from a lethal
infection. Six of the treated mice survived over nine months, three without further treatment. Three mice that had entered the chronic stage of
infection were retreated with a 20-d regimen. At the conclusion of the experiments, five of the six mice had repeated negative hemacultures, indicative of parasitological cure. Studies of the effect of inhibitors on the intracellular amastigote form suggest that the life cycle is interrupted because of inhibitor arrest of normal autoproteolytic
cruzain processing at the level of the Golgi complex. Parasites recovered from the hearts of treated mice showed the same abnormalities 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 animals to selectively arrest a
parasitic infection.