The peptidases of Trypanosoma cruzi: Digestive enzymes, virulence factors, and mediators of autophagy and programmed cell death

Reversible Cysteine Protease Inhibitors Show Promise for a Chagas Disease Cure

“…While a slow killing mechanism may be possible at these lower concentrations due to impairment of the parasite (20,50), one could also invoke mechanisms of action that are only possible in vivo, such as inhibition of direct tissue and macrophage invasion (49,51), reduction of parasite-evoked inflammatory edema that may enable persistent parasitism (52,53,54), and abrogation of host immune evasion (55,56). These biological effects are believed to be the result of cruzipain, which is tethered, secreted, or present in secluded sites of the host-parasite interface (16,17,19,28,51,53) and would be readily accessible to cruzipain inhibitors in the blood compartment. The 1 to 2 nM IC 50 s of these compounds versus cruzipain and their nanomolar drug blood concentrations suggest that the efficacy observed in vivo is significantly driven by inhibition of extracellular cruzipain.…”

“…The cysteine protease cruzipain, a member of the papain family, is essential for the viability and virulence of T. cruzi, and thus inhibitors of cruzipain are considered promising agents for Chagas disease therapies (14,15,16,17,18,19). Studies with irreversible cruzipain inhibitors have shown the biochemical impact of inhibiting cruzipain on T. cruzi.…”

The functional and pathologic relevance of autophagy proteases

“…Infections by parasites including Trypanosoma cruzi, which causes Chagas disease, or Leishmania major, responsible for leishmaniasis, are different from those caused by other pathogens, as these eukaryotic organisms also utilize autophagy (97). In fact, the activity of their Atg4 orthologs is essential for their survival, differentiation, and virulence, and new therapeutic strategies targeting these proteases could block or slow the infection (98)(99)(100)(101).…”

Immunocytochemistry of Proteases in the Study of Leishmania Physiology and Host-Parasite Interaction

“…This was the first study that reports the presence of serine peptidase activity in Leishmania and even more an oligopeptidase (Andrade et al, 1998). It is important to consider that Trypanosoma species do not express enzymes showing serine protease activities, but only serine oligopeptidases with specific functions in many steps of mammalian cell invasion (Silva-López et al, 2008;Alvarez et al, 2011).…”