Aspartic Peptidases of Human Pathogenic Trypanosomatids: Perspectives and Trends for Chemotherapy

Abstract

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.

Parasite Cathepsin D-Like Peptidases and Their Relevance as Therapeutic Targets

“…These studies have highlighted the need to identify and functionally characterize APD target enzyme(s) before they are tested as chemotherapeutic targets [11]. The finding that HIV protease inhibitors (HIV PIs) have significant effects on parasitic kinetoplastida is paradoxical because APD coding sequences are absent from the genomes of Trypanosoma cruzi, Trypanosoma brucei, and Leishmania braziliensis [11], and most likely reflects off-target effects.…”

“…These studies have highlighted the need to identify and functionally characterize APD target enzyme(s) before they are tested as chemotherapeutic targets [11]. The finding that HIV protease inhibitors (HIV PIs) have significant effects on parasitic kinetoplastida is paradoxical because APD coding sequences are absent from the genomes of Trypanosoma cruzi, Trypanosoma brucei, and Leishmania braziliensis [11], and most likely reflects off-target effects. In support, there is experimental evidence that HIV PIs can interact with non-A1 family aspartic peptidases [12], and some clan AD, family A22 (presenilin-like) and clan AA, family A28 (Ddi-1-like) protease coding genes are found in the above-listed genomes [13].…”

“…In support, there is experimental evidence that HIV PIs can interact with non-A1 family aspartic peptidases [12], and some clan AD, family A22 (presenilin-like) and clan AA, family A28 (Ddi-1-like) protease coding genes are found in the above-listed genomes [13]. Importantly, off-target inhibition of cytochrome P450s by HIV PIs is known to occur in mammalian systems [14], and should not be ruled out as a potential explanation [11].…”

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

“…For example, K777, a peptidase inhibitor of the major cysteine proteinase of T. cruzi known as cruzain or cruzipain, became a potent candidate to advance into clinical trials in view of its effective activity against different strains of T. cruzi 20 , including its efficiency in protecting against cardiac damage in a canine experimental model 21 and in response to multi-drug therapy 22 . Aspartic peptidase from T. cruzi has also been proposed as a drug target since treatment of epimastigotes with pepstatin A, an aspartic peptidase inhibitor, inhibited parasite proliferation, induced morphological changes with detachment of flagellum, and increased expression of gp63 23 . Moreover, matrix metallopeptidase-9 homologues detected in T. cruzi may be a potential therapeutic target, since they could be able to induce a reduction in the expression of matrix metallopeptidase-9 (MMP-9) during interaction with host cells 24,25 .…”

Decoding the Anti-Trypanosoma cruzi Action of HIV Peptidase Inhibitors Using Epimastigotes as a Model

“…The characterization of peptidases is of interest to understand their characteristics and also to assess their roles in parasitic infections, exploring them as new chemotherapeutic targets [9] . In this context, aspartic peptidases have been identified in different classes of infectious agents, participating in various physiological and pathological events [10] , [11] . However, the only aspartic peptidase inhibitors approved for chemotherapy are the ones used in anti-HIV therapy [10] .…”