Repositioning of HIV Aspartyl Peptidase Inhibitors for Combating the Neglected Human Pathogen Trypanosoma cruzi

Abstract

Chagas disease, caused by the flagellate parasite Trypanosoma cruzi, is a wellknown neglected tropical disease. This parasitic illness affects 6-7 million people and can lead to severe myocarditis and/or complications of the digestive tract. The changes in its epidemiology facilitate co-infection with the Human Immunodeficiency Virus (HIV), making even more difficult the diagnosis and prognosis. The parasitic infection is reactivated in T. cruzi/HIV co-infection, with the appearance of unusual manifestations in the chronic phase and the exacerbation of classical clinical signs. The therapeutic arsenal to treat Chagas disease, in all its clinical forms, is restricted basically to two drugs, benznidazole and nifurtimox. Both drugs are extremely toxic and the therapeutic efficacy is still unclear, making the clinical treatment a huge issue to be solved. Therefore, it seems obvious the necessity of new tangible approaches to combat this illness. In this sense, the repositioning of approved drugs appears as an interesting and viable strategy. The discovery of Human Immunodeficiency Virus Aspartyl Peptidase Inhibitors (HIV-PIs) represented a milestone in the treatment of Acquired Immune Deficiency Syndrome (AIDS) and, concomitantly, a marked reduction in both the incidence and prevalence of important bacterial, fungal and parasitic co-infections was clearly observed. Taking all these findings into consideration, the present review summarizes the promising and beneficial data concerning the effects of HIV-PIs on all the evolutionary forms of T. cruzi and in important steps of the parasite’s life cycle, which highlight their possible application as alternative drugs to treat Chagas disease.

Lopinavir and Nelfinavir Induce the Accumulation of Crystalloid Lipid Inclusions within the Reservosomes of Trypanosoma cruzi and Inhibit Both Aspartyl-Type Peptidase and Cruzipain Activities Detected in These Crucial Organelles

“…Corroborating these findings, the in vitro activity of the partially purified cruzipain was abolished by saquinavir at 100 μM [ 30 ]. In this same line of thinking, nelfinavir at 10 μM reduced the cruzipain-like activity present in T. cruzi trypomastigotes total extracts by approximately 32% [ 6 ].…”

“…However, the exact mechanism of how this phenomenon occurs in T. cruzi is completely unknown. Some possibilities of nonspecific toxic effects of HIV-PIs have been raised, but we can also presume that the aspartyl-type peptidases produced by the parasite can be a target and may be directly/indirectly involved in this lipid imbalance [ 6 ].…”

“…The docking assays revealed that HIV-PIs bind to the active site of the enzyme, with lopinavir and ritonavir having greater affinity [ 27 ]. Indeed, several works have demonstrated the potential inhibition of HIV-PIs on aspartyl-type peptidases produced by both epimastigotes and trypomastigotes of T. cruzi ; however, these enzymatic assays were conducted with the crude extract of the parasites, without distinguishing where these enzymes could be localized (reviewed in [ 6 ]). Here, we found an enzymatic activity reported to aspartyl-type peptidases mainly in the lipid-poor reservosomes (Fraction B2) of T. cruzi , where this activity was strongly inhibited by lopinavir and nelfinavir.…”

“…In addition to impairing the replication and maturation of viral particles [ 1 ], the introduction of HIV-PIs to highly active antiretroviral therapy (HAART) also had an impact on opportunistic coinfections [ 2 , 3 , 4 , 5 ]. In this line, our research group studied the repositioning of HIV-PIs against Trypanosoma cruzi , where the most effective PIs, lopinavir and nelfinavir, had a huge effect on all life forms of the parasite (for a comprehensive reading, see the review [ 6 ]). One of the most common effects triggered by the HIV-PIs was alterations in the parasite’s lipid metabolism, where both lopinavir and nelfinavor induced a significant augment in the neutral lipid storage, as judged by incubation with Nile red fluorophore [ 6 ].…”

Chagas Disease Treatment: From New Therapeutic Targets to Drug Discovery and Repositioning

“…Sangenito et al [5] introduce the aspartyl peptidase inhibitors used to treat the infection with the human immunodeficiency virus (HIV) as a drug repositioning strategy. Co-infection of patients with HIV with other microorganisms, such as protozoan parasites, is common and the use of HIV peptidase inhibitors evidenced a decrease both in prevalence and incidence of these co-infections.…”