The major goal of our research is to develop and test specific inhibitors of Trypanosoma cruzi proteinase that we hypothesize is critical to the pathogenesis of Chagas' disease. T. cruzi elaborates a cysteine proteinase which we hypothesize is required for the metabolism of the parasite within cardiac cells, and transformation between stages of the parasite life cycle. We have tested synthetic proteinase inhibitors which are effective against the enzyme, in cell culture to see the effect on parasite replication in mammalian cells. P34081 (Mu-Phe-homophe-FMK) used as our standard showed inhibition of the parasite replication. However, when the drug pressure was relived after ten days of treatment the parasites resume replication. In contrast, P35027 not only arrested parasite growth but also had trypanocidal effect clearing the cell culture of infection after 14 days of treatment at 20 5M concentration. We have now tested P35027 compound in a preliminary animal trial. No adverse effects were observed in mice treated with 2 mg/day for as long as 45 days with the pseudopeptide inhibitor. A preliminary trial showed that two 1-mg injections daily of P35027 reduced the parasitemia levels in T. cruzi-infected mice, and extends the survival of mice infected with 500 times the lethal dose (Fig. B). Survival of the mice challenged with a lower lethal dose of infection was greatly extended with doses slightly higher (3 mg/day/mice) during a 12 day period. Sometreated animals survived more than five months after infection without detectable parasitemia (Fig. C). However, A more extensive animal trial, to optimize drug dosage and treatment schedule to increase the efficacy of the inhibitors are necessary before cure can be achieved.
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