Aspartic Peptidases of Human Pathogenic Trypanosomatids: Perspectives and Trends for Chemotherapy
L. O. Santos, A. S. Garcia-Gomes, M. Catanho, C. L. Sodre, A. L.S. Santos, M. H. Branquinha and C. M. d’Avila-Levy
Pages 3116-3133 (18)
Aspartic peptidases are proteolytic enzymes present in many organisms like vertebrates, plants, fungi, protozoa
and in some retroviruses such as human immunodeficiency virus (HIV). These enzymes are involved in important metabolic
processes in microorganisms/virus and play major roles in infectious diseases. Although few studies have been performed
in order to identify and characterize aspartic peptidase in trypanosomatids, which include the etiologic agents of
leishmaniasis, Chagas’ disease and sleeping sickness, some beneficial properties of aspartic peptidase inhibitors have been
described on fundamental biological events of these pathogenic agents. In this context, aspartic peptidase inhibitors (PIs)
used in the current chemotherapy against HIV (e.g., amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir)
were able to inhibit the aspartic peptidase activity produced by different species of Leishmania. Moreover, the treatment
of Leishmania promastigotes with HIV PIs induced several perturbations on the parasite homeostasis, including loss of the
motility and arrest of proliferation/growth. The HIV PIs also induced an increase in the level of reactive oxygen species
and the appearance of irreversible morphological alterations, triggering parasite death pathways such as programed cell
death (apoptosis) and uncontrolled autophagy. The blockage of physiological parasite events as well as the induction of
death pathways culminated in its incapacity to adhere, survive and escape of phagocytic cells. Collectively, these results
support the data showing that parasites treated with HIV PIs have a significant reduction in the ability to cause in vivo infection.
Similarly, the treatment of Trypanosoma cruzi cells with pepstatin A showed a significant inhibition on both aspartic
peptidase activity and growth as well as promoted several and irreversible morphological changes. These studies
indicate that aspartic peptidases can be promising targets in trypanosomatid cells and aspartic proteolytic inhibitors can be
benefic chemotherapeutic agents against these human pathogenic microorganisms.
Alternative chemotherapy, aspartic peptidases, Chagas’ disease, HAART, HIV, HIV peptidase inhibitors, Leishmania,
leishmaniasis, pathogenesis, peptidases, proteolytic inhibitors, Trypanosoma, virulence.
Laboratorio de Biologia Molecular e Doencas Endemicas, Instituto Oswaldo Cruz (IOC), Pavilhao Leonidas Deane, Fundacao Oswaldo Cruz (FIOCRUZ), Av Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, Brazil, CEP 21040-360.