Calpains: Potential Targets for Alternative Chemotherapeutic Intervention Against Human Pathogenic Trypanosomatids

Abstract

Abstract:The treatment for both leishmaniasis and trypanosomiasis, which are severe human infections caused by trypanosomatids belonging to Leishmania and Trypanosoma genera, respectively, is extremely limited because of concerns of toxicity and efficacy with the available anti-protozoan drugs, as well as the emergence of drug resistance. Consequently, the urgency for the discovery of new trypanosomatid targets and novel bioactive compounds is particularly necessary. In this context, the investigation of changes in parasite gene expression between drug resistant/sensitive strains and in the up-regulation of virulence-related genes in infective forms has brought to the fore the involvement of calpain-like proteins in several crucial pathophysiological processes performed by trypanosomatids. These studies were encouraged by the publication of the complete genome sequences of three human pathogenic trypanosomatids, Trypanosoma brucei, Trypanosoma cruzi and Leishmania major, which allowed in silico analyses that in turn directed the identification of numerous genes with interesting chemotherapeutic characteristics, including a large family of calpain-related proteins, in which to date 23 genes were assigned as calpains in T. brucei, 40 in T. cruzi and 33 in L. braziliensis. In the present review, we intend to add to these biochemical/biological reports the investigations performed upon the inhibitory capability of calpain inhibitors against human pathogenic trypanosomatids.

Susceptibility of Phytomonas serpens to calpain inhibitors in vitro: interference on the proliferation, ultrastructure, cysteine peptidase expression and interaction with the invertebrate host

“…Many experimental evidences have demonstrated the important roles that calpain-like proteins (CALPs) may play in trypanosomatids, such as the stage-specific expression in distinct parasites and the differential expression of CALPs in drug-resistant strains (Branquinha et al 2013). Calpains are neutral, calcium-dependent cysteine peptidases that form one of the most important proteolytic systems of mammalian cells (Goll et al 2003, Ono & Sorimachi 2012).…”

“…Numerous functions related to signal transduction, cell motility, differentiation, proliferation, gene expression and apoptosis have been postulated for calpains in the human body (Goll et al 2003, Ono & Sorimachi 2012). The large and diverse family of CALPs detected in trypanosomatids (Ersfeld et al 2005) was categorised into five groups, based on their structural features, but the absence of amino acid residues essential for catalytic activity and the moderate overall degree of sequence identity with human calpains suggest that most of these CALPs do not have proteolytic activity (Ersfeld et al 2005, Branquinha et al 2013). Non-proteolytic CALPs are likely to function as structural elements and in regulatory processes, and as such a universal function of calpains and CALPs appears to be that of a scaffold by interacting with various molecules, as shown by their wide range of substrate specificity (Tonami et al 2007).…”

“…Some studies from our group using immunoblotting analysis showed that the anti-Dm-calpain antibody, specific against Drosophila melanogaster calpain (Emori & Saigo 1994), strongly recognised a polypeptide of approximately 80 kDa in the spent culture medium of the insect trypanosomatid Angomonas deanei (formely Crithidia deanei ), in Leishmania amazonensis promastigotes, in Herpetomonas samuelpessoai promastigotes and paramastigotes as well as in T. cruzi epimastigotes (Branquinha et al. 2013).…”

“…2013). In addition, we also reported that MDL28170 was able to interfere in many aspects of T. cruzi life cycle, which includes the reduction of the viability of infective trypomastigote forms and their interaction with macrophages, besides the inhibition of epimastigotes adhesion to the insect midgut and the differentiation process into metacyclic trypomastigotes (Branquinha et al 2013). These data point to the importance of the studies concerning the effects of calpain inhibitors in different stages of the parasites’ metabolism.…”

Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease

“…Given the key role of peptidases in biological systems, these enzymes have been considered a potential therapeutic target against infectious agents 17,18 . Different classes of peptidases participate in important biological events in the T. cruzi life cycle, including processes of invasion, differentiation, proliferation as well as mechanisms of escape from host immune responses 19 .…”