Cysteine protease inhibitors as chemotherapy: Lessons from a parasite target

Papain family cysteine proteases are key factors in the pathogenesis of can cer invasion, arthritis, osteoporosis, and microbial infections. Targeting this enzyme family is therefore one strategy in the development of new chem otherapy for a number of diseases. Little is known, however, about the effi cacy, selectivity, and safety of cysteine protease inhibitors in cell cultu re or in vivo. We now report that specific cysteine protease inhibitors kil l Leishmania parasites in vitro, at concentrations that do not overtly affe ct mammalian host cells. Inhibition of Leishmania cysteine protease activit y was accompanied by defects in the parasite's lysosome/endosome compartmen t resembling those seen in lysosomal storage diseases. Colocalization of an ti-protease antibodies with biotinylated surface proteins and accumulation of undigested debris and protease in the flagellar pocket of treated parasi tes were consistent with a pathway of protease trafficking from flagellar p ocket to the lysosome/endosome compartment, The inhibitors were sufficientl y absorbed and stable in vivo to ameliorate the pathology associated with a mouse model of leishmania infection.