Peptidase Inhibitors as a Possible Therapeutic Strategy for Chagas Disease

Giseli      Capaci Rodrigues; Alcino      Palermo Aguiar; Joao      Lidio da Silva Goncalves Vianez; Andrew      Macrae; Ana      Cristina Nogueira de Melo; Alane      Beatriz Vermelho

Abstract

Chagas disease, caused by Trypanosoma cruzi, is one of the neglected parasitic tropical diseases affecting thirteen million people annually. At present, there are only two compounds used in the clinical treatment to this disease and they were introduced in the 1960s and 1970s. Nifurtimox and Benznidazole have limited effectiveness and serious side effects. New strategies and targets for an effective chemotherapy for American trypanosomiasis need to be developed. Within this framework, the peptidases have aroused great interest as a chemotherapeutic target against Chagas disease. This is because some T. cruzi peptidases have been implicated, among other processes, in host-parasite interactions and parasitic survival in their hosts like cruzipain (cysteine peptidase) and prolyl oligopeptidase (serine peptidase). Besides, some of these peptidases are expressed in all life cycle stages of the parasite and it is essential for replication of the intracellular forms. The inhibition of these enzymes has shown high anti-T. cruzi activity in vitro and in vivo. In this review, we describe some peptidase inhibitors that have potential in the fight against T. cruzi. Emphasis is given to cruzipain inhibitors and the inhibition mechanism proposed for some them. Among these inhibitors are peptidyl irreversible (halomethyl ketone, diazomethane ketones and vinyl sulfones derivatives) and reversible (aryl ureas and oxadiazoles derivatives) inhibitors, besides non-peptidyl inhibitors (thiosemicarbazones, triazole, triazine nitriles and vinyl sulfones derivatives). Some serine peptidase inhibitors are also described (tic-based peptides, prolylprolylisoxazoles and prolylprolylisoxazolines). Other peptidases, including the metallo-, aspartic and threonine (proteosome) peptidases are discussed and along with blocking cruzipain are targets for future therapeutic strategies.

Keywords: American trypanosomiasis, Chagas disease, drug targets, peptidases, peptidase inhibitors, Trypanosoma cruzi, parasitic tropical diseases, therapeutic strategies, Peptide-Based Irreversible Inhibitors, Peptide-Based Reversible Inhibitors