title: Cysteine protease inhibitors as chemotherapy: lessons from a parasite target.
abstract: Papain family cysteine proteases are key factors in the pathogenesis of cancer invasion, arthritis, osteoporosis, and microbial infections. Targeting this enzyme family is therefore one strategy in the development of new chemotherapy for a number of diseases. Little is known, however, about the efficacy, selectivity, and safety of cysteine protease inhibitors in cell culture or in vivo. We now report that specific cysteine protease inhibitors kill Leishmania parasites in vitro, at concentrations that do not overtly affect mammalian host cells. Inhibition of Leishmania cysteine protease activity was accompanied by defects in the parasite's lysosome/endosome compartment resembling those seen in lysosomal storage diseases. Colocalization of anti-protease antibodies with biotinylated surface proteins and accumulation of undigested debris and protease in the flagellar pocket of treated parasites were consistent with a pathway of protease trafficking from flagellar pocket to the lysosome/endosome compartment. The inhibitors were sufficiently absorbed and stable in vivo to ameliorate the pathology associated with a mouse model of Leishmania infection.
authors.affiliation: Department of Pathology, University of California, San Francisco, CA 94143, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Selzer
authors.forename: S
authors.initials: S
authors.lastname: Pingel
authors.forename: I
authors.initials: I
authors.lastname: Hsieh
authors.forename: B
authors.initials: B
authors.lastname: Ugele
authors.forename: V J
authors.initials: VJ
authors.lastname: Chan
authors.forename: J C
authors.initials: JC
authors.lastname: Engel
authors.forename: M
authors.initials: M
authors.lastname: Bogyo
authors.forename: D G
authors.initials: DG
authors.lastname: Russell
authors.forename: J A
authors.initials: JA
authors.lastname: Sakanari
authors.forename: J H
authors.initials: JH
authors.lastname: McKerrow
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D018320:Leishmania major / Q000187:drug effects* / Q000648:ultrastructure; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron
chemical_list: D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors