Cruzipain: An Update on its Potential as Chemotherapy Target against the Human Pathogen Trypanosoma cruzi

Abstract

Chagas' disease is one of the most impactful and prevalent neglected tropical diseases in the Americas, specially affecting the poor and underdeveloped areas in Latin America. Aggravating this scenario, the medicines used in the current chemotherapy are old, toxic and present a low efficacy to treat the chronic stage of this disease. In addition, resistant strains of Trypanosoma cruzi, the etiological agent, are frequently reported. So, there is an imperative requirement for novel chemotherapeutic options to treat this debilitating disease. In this context, peptidases have emerged as potential targets and, consequently, proteolytic inhibitors have confirmed to be valuable drugs against several human pathologies. In this line of thinking, T. cruzi produces a major multifunctional cysteine peptidase, named cruzipain, which directly and/or indirectly orchestrates several physiological and pathological processes, which culminate in a successful parasitic infection. Taken together, these findings point out that cruzipain is one of the most important targets for driving a chemotherapy approach against the human pathogen T. cruzi. The present review summarizes some of the recent advances and failures in this area, with particular emphasis on recently published studies.

Knockout of the gamma subunit of the AP-1 adaptor complex in the human parasite Trypanosoma cruzi impairs infectivity and differentiation and prevents the maturation and targeting of the major protease cruzipain

“…Cruzipain is a differentially glycoprotein expressed during the T . cruzi life cycle, it has higher activity in epimastigotes, where it is found in the Golgi as a pre-proprotein [ 16 , 62 ]. Cruzipain is then targeted to reservosomes independent from the addition of mannose-6-phosphate (M6P) residues [ 3 , 10 ], which target lysosomal hydrolases to endosomes in other eukaryotes [ 53 ].…”

“…cruzi , is highly expressed in epimastigotes [ 10 ] and accumulates in reservosomes [ 3 ] along with its inhibitor, chagasin [ 11 ]. Cruzipain plays an important role in parasite nutrition, differentiation and infectivity [ 12 – 16 ], and it is synthesized and processed in the endoplasmic reticulum/Golgi complex. However, it is not yet clear how cruzipain is targeted to reservosomes [ 17 ].…”

Papain-Like Proteases as Coronaviral Drug Targets: Current Inhibitors, Opportunities, and Limitations

“…This made them perspective targets for inhibition and induced intensive study of PLCPs over the last years. Multiple inhibitors have been developed for human cysteine cathepsins, which play a crucial role in tumor progression [ 10 , 11 , 12 ], and for pathogen PLCPs, such as cruzipain from Trypanosoma cruzi and falcipain from Plasmodium falciparum [ 13 , 14 ].…”

Interactions between Trypanosoma cruzi Secreted Proteins and Host Cell Signaling Pathways

“…Taken together, the data suggests that cruzipain is a potential pharmaceutical target as it may have an essential role in the pathogenesis of Chagas disease ( Guiñazú et al, 2007 ; Doyle et al, 2011 ). Based on this evidence, cruzipain inhibitors are considered promising anti- T. cruzi chemotherapeutic agents ( Ndao et al, 2014 ; Branquinha et al, 2015 ). Irreversible cruzipain inhibitors, such as the prototype molecule K777 (also known as K11777) have been efficacious in experimental models of T. cruzi infection ( Engel et al, 1998 ; Barr et al, 2005 ; Doyle et al, 2011 ).…”