Deciphering the effects of nelfinavir and lopinavir on epimastigote forms of Trypanosoma cruzi

Sangenito, Leandro S.; Guedes, Arthur A. de; Gonçalves, Diego de Souza; Seabra, Sérgio Henrique; d’Avila-Levy, Claudia M.; Santos, André Luis Souza dos; Branquinha, Marta H.

doi:10.1016/j.parint.2017.03.009

Cited by 6 publications

(2 citation statements)

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“…Previously, our research group observed the influence of lopinavir and nelfinavir on the accumulation and distribution of neutral lipids in T. cruzi epimastigotes. The visualization of lopinavir-/nelfinavir-treated parasites under fluorescence microscopy revealed the presence of many Nile red-stained lipid bodies, which were randomly distributed throughout the cytoplasm [ 22 ]. Subsequently, TEM analyses revealed the formation of lipid droplets in close contact with the endoplasmic reticulum of T. cruzi trypomastigotes treated with both lopinavir and nelfinavir.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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Several research groups have explored the repositioning of human immunodeficiency virus aspartyl peptidase inhibitors (HIV-PIs) on opportunistic infections caused by bacteria, fungi and protozoa. In Trypanosoma cruzi, HIV-PIs have a high impact on parasite viability, and one of the main alterations promoted by this treatment is the imbalance in the parasite’s lipid metabolism. However, the reasons behind this phenomenon are unknown. In the present work, we observed by transmission electron microscopy (TEM) that the treatment of T. cruzi epimastigotes with the HIV-PIs lopinavir and nelfinavir induced a huge accumulation of crystalloid-shaped lipids within the reservosomes, most of them deforming these key organelles. As previously reported, those structures are characteristic of lipid inclusions formed mostly of cholesterol and cholesterol-esters. The fractionation of nontreated epimastigotes generated two distinct fractions enriched in reservosomes: one mostly composed of lipid inclusion-containing reservosomes (Fraction B1) and one where lipid inclusions were much less abundant (Fraction B2). Interestingly, the extract of Fraction B2 presented enzymatic activity related to aspartyl-type peptidases 3.5 times higher than that found in the extract obtained from Fraction B1. The cleavage of cathepsin D substrate by this class of peptidases was strongly impaired by pepstatin A, a prototypical aspartyl PI, and the HIV-PIs lopinavir and nelfinavir. In addition, both HIV-PIs also inhibited (to a lesser extent) the cruzipain activity present in reservosomes. Finally, our work provides new evidence concerning the presence and supposed participation of aspartyl peptidases in T. cruzi, even as it adds new information about the mechanisms behind the alterations promoted by lopinavir and nelfinavir in the protozoan.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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“…The marked improvement in the life expectancy of AIDS sufferers after the incorporation of HIV aspartic peptidase inhibitors (HIV IPs) into the drug cocktail, the so-called highly active anti-retroviral therapy (HAART), was due to reduction in viremia, recovery of the immune response and a direct action on opportunistic pathogens [reviewed in 3 ]. The last effect has been extensively demonstrated in Trypanosoma cruzi by our research group [ 3 , 12 – 14 ] and others [ 15 ], although the mode of action and intracellular target of the compounds are still unknown and have been a matter of extensive research [ 3 , 14 , 16 , 17 ]. Here, we identified in the genome of T. cruzi , CL-Brener strain, a homologue of the HIV retroviral peptidase and selected a crystalized protein for generating a three dimensional model, which was aligned with HIV aspartyl peptidase.…”

Section: Introductionmentioning

confidence: 99%

Docking simulation between HIV peptidase inhibitors and Trypanosoma cruzi aspartyl peptidase

et al. 2018

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ObjectiveThe low investment in research, diagnosis and treatment are factors that contribute to the continuity of Chagas’ disease as a neglected tropical diseases (NTDs). In this context, the repositioning of drugs represents a useful strategy, in the search for new chemotherapeutic approaches for NTDs. HIV aspartic peptidase inhibitors (HIV IPs) are good candidates for drug repurposing. Here, we modeled the three dimensional structure of an aspartyl peptidase of Trypanosoma cruzi, the causative agent of Chagas’ disease, aligned it to the HIV aspartyl peptidase and performed docking binding assays with the HIV PIs.ResultsThe 3D structure confirmed the presence of acid aspartic residues, which are critical to enzyme activity. The docking experiment revealed that HIV IPs bind to the active site of the enzyme, being ritonavir and lopinavir the ones with greater affinity. Benznidazole presented the worst binding affinity, this drug is currently used in Chagas’ disease treatment and was included as negative control. These results together with previous data on the trypanocidal effect of the HIV PIs support the hypothesis that a T. cruzi aspartyl peptidase can be the intracellular target of these inhibitors. However, the direct demonstration of the inhibition of T. cruzi aspartyl peptidase activity by HIV PIs is still a goal to be persuaded.Electronic supplementary materialThe online version of this article (10.1186/s13104-018-3927-z) contains supplementary material, which is available to authorized users.

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Primary evidence of the mechanisms of action of HIV aspartyl peptidase inhibitors on Trypanosoma cruzi trypomastigote forms

Sangenito

Menna-Barreto

Oliveira

et al. 2018

International Journal of Antimicrobial Agents

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Deciphering the effects of nelfinavir and lopinavir on epimastigote forms of Trypanosoma cruzi

Cited by 6 publications

References 39 publications

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

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

Docking simulation between HIV peptidase inhibitors and Trypanosoma cruzi aspartyl peptidase

Primary evidence of the mechanisms of action of HIV aspartyl peptidase inhibitors on Trypanosoma cruzi trypomastigote forms

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