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 lysosome͞endosome 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 f lagellar pocket of treated parasites were consistent with a pathway of protease trafficking from f lagellar pocket to the lysosome͞endosome compartment. The inhibitors were sufficiently absorbed and stable in vivo to ameliorate the pathology associated with a mouse model of Leishmania infection.

Autophagy Is Involved in Nutritional Stress Response and Differentiation in Trypanosoma cruzi

“…Knocking out aspartic protease cathepsin D or, simultaneously, cathepsins B and L resulted in defects in autophagy and accumulation of autophagosomes (53). A similar effect was also observed in Leishmania, where inhibition of cysteine peptidases (CPA, CPB, CPC) homologous to cruzipain and cysteine cathepsins with broad spectrum reversible or irreversible inhibitors, which killed the parasite, was accompanied with defects in the lysosomal compartment resembling lysosomal storage disease (54). Moreover, CPA and CPB from Leishmania mexicana were recently found to be essential for both autophagosome degradation and differentiation of that parasite.…”

Successful Therapy of Lethal Murine Visceral Leishmaniasis with Cystatin Involves Up-Regulation of Nitric Oxide and a Favorable T Cell Response

“…In contrast, the administration of vinyl sulfone inhibitor, an irreversible cysteine protease inhibitor, to a mouse model of cutaneous leishmaniasis did not result in a switch from Th2 to Th1 cytokines. It exerted its antileishmanial effect by inhibiting parasite replication (44). In the present study, cure as well as resistance acquired by susceptible BALB/c mice due to combination chemotherapy were attributed to two mechanisms: 1) the direct action of cystatin for the induction of the NO that kills the parasite; and 2) the switch of CD4 ϩ T cell-mediated immune responses from the diseasepromoting Th2 to the protective Th1 type.…”

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

“…Specific CP inhibitors not only can kill L. major in vitro, but also can cure L. major infection in BALB/c mice (53). In fact, inhibitors of CPs from T. cruzi (54), T. brucei (55), and Plasmodium (56,57) have demonstrated efficacy in preliminary animal studies, and K11777, a CP inhibitor of the T. cruzi enzyme cruzipain, will enter clinical trials for Chagas disease very soon (32).…”