Trypanocidal effect of cysteine protease inhibitors in vitro and in vivo in experimental Chagas disease

Endemic in most American countries, Chagas' disease causes high morbidity a nd mortality. Recent experimental and clinical evidence shows the importanc e of chemotherapy in both the acute and chronic phases of this disease. How ever, treatment is yet limited by the toxicity associated to available drug s. This review describes the design, evolution, and selection of dipeptides that interrupt the intracellular cycle of T. cruzi and cure acute experime ntal infections in laboratory animals. Peptido-mimetic inhibitors specifica lly bind cruzain, a T. cruzi cystein protease. The inhibitors cause alterat ions in the Golgi complex and ER, accumulation of unprocessed enzyme within Golgi cisternae, and decrease of mature cruzain within lysosomes. The most effective compound, N-Pip-F-hF-VS phi, cured an acute lethal infection in experimental animals. Myocardial lesions, lymphocyte infiltration and intra cellular amastigote clusters were absent in treated animals. Preliminary to xicology and pharmacokinetic analyses suggest the lack of toxicity associat ed to high doses and prolonged treatment regimes. Protease inhibitors may s oon become good chemotherapeutic alternatives for acute and chronic Chagas' disease.