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Background: Parasitic human infectious diseases are a worldwide health problem due to the increased resistance to conventional drugs. For this reason, the identification of novel molecular targets and the discovery of new chemotherapeutic agents are urgently required. Metalo-aminopeptidases are promising targets in parasitic infections. They participate in crucial processes for parasite growth and pathogenesis. Objective: In this review, we describe the structural, functional and kinetic properties, and inhibitors, of several parasite metalo-aminopeptidases, for their use as targets in parasitic diseases. Conclusion: Plasmodium falciparum M1 and M17 aminopeptidases are essential enzymes for parasite development, and M18 aminopeptidase could be involved in hemoglobin digestion and erythrocyte invasion and egression. Trypanosoma cruzi, T. brucei and Leishmania major acidic M17 aminopeptidases can play a nutritional role. T. brucei basic M17 aminopeptidase down-regulation delays the cytokinesis. The inhibition of Leishmania basic M17 aminopeptidase could affect parasite viability. L. donovani methionyl aminopeptidase inhibition prevents apoptosis but not the parasite death. Decrease in Acanthamoeba castellanii M17 aminopeptidase activity produces cell wall structural modifications and encystation inhibition. Inhibition of Babesia bovis growth is probably related to the inhibition of the parasite M17 aminopeptidase, probably involved in host hemoglobin degradation. Schistosoma mansoni M17 aminopeptidases inhibition may affect parasite development, since they could participate in hemoglobin degradation, surface membrane remodeling and eggs hatching. Toxoplasma gondii M17 aminopeptidase inhibition could attenuate parasite virulence, since it is apparently involved in the hydrolysis of cathepsin Cs- or proteasome-produced dipeptides and/or cell attachment/invasion processes. These data are relevant to validate these enzymes as targets.

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Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC50 = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC50 = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.

Several microbial metalo-aminopeptidases are emerging as novel targets for the treatment of human infectious diseases. Some of them are well validated as targets and some are not; some are essential enzymes and others are important for virulence and pathogenesis. For another group, it is not clear if their enzymatic activity is involved in the critical functions that they mediate. But one aspect has been established: they display relevant roles in bacteria and protozoa that could be targeted for therapeutic purposes. This work aims to describe these biological functions for several microbial metalo-aminopeptidases.