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

dc.creatorSangenito, Leandro S.
dc.creatorMenna-Barreto, Rubem F. S.
dc.creatorOliveira, Ana Carolina
dc.creatord`Avila-Levy, Claudia M.
dc.creatorBranquinha, Marta H.
dc.creatorSantos, André L. S.
dc.date2018-10-11T12:09:56Z
dc.date2018-10-11T12:09:56Z
dc.date2018
dc.date.accessioned2023-09-26T22:16:27Z
dc.date.available2023-09-26T22:16:27Z
dc.identifierSANGENITO, Leandro S. et al. Primary evidence of the mechanisms of action of HIV aspartyl peptidase inhibitors on Trypanosoma cruzi trypomastigote forms. International Journal of Antimicrobial Agents, v.52, p.185–194, 2018.
dc.identifier0924-8579
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/29506
dc.identifier10.1016/j.ijantimicag.2018.03.021
dc.identifier1872-7913
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8877156
dc.descriptionThe development of HIV aspartyl peptidase inhibitors (HIV-PIs) and their introduction into AIDS therapy preceded a significant decrease in the incidence, morbidity and mortality of relevant protozoan co-infections. However, few data are available about how HIV-PIs act on pathogenic parasites, such as Trypanosoma cruzi, the etiological agent of Chagas disease. Therefore, the aim of the present work was to evaluate different physiological aspects of the treatment of the infective trypomastigote forms of T. cruzi with the HIV-PIs, nelfinavir and lopinavir. At the LD50/4 h doses, both HIV-PIs significantly reduced the trypomastigote size and markedly increased the granularity/complexity. Transmission electron microscopy analysis associated to biochemical assays permitted definition of the main HIV-PIs targets in the parasite. Lopinavir and nelfinavir induced (i) plasma membrane shedding, particularly in the flagellar region, which drastically affected parasite integrity; (ii) strong mitochondrial swelling with rare matrix fragmentation, which were linked to severely reduced hydrolytic activity of dehydrogenases and organelle membrane depolarization; (iii) increased generation of reactive oxygen species (ROS); (iv) dilation of both nuclear envelope (without DNA disruption) and endoplasmic reticulum (with formation of autophagosomes), and (v) accumulation of intracellular lipid droplets, revealing a typical lipid metabolism disorder. Collectively, our study demonstrated that nelfinavir and lopinavir target vital cellular structures of trypomastigotes, culminating in irreversible metabolic injuries that lead to T. cruzi death.
dc.description2030-01-01
dc.formatapplication/pdf
dc.languageeng
dc.publisherElsevier
dc.rightsrestricted access
dc.subjectTrypanosoma cruzi
dc.subjectInibidores da aspartilpeptidase do HIV
dc.subjectModo de ação
dc.subjectAlterações fisiológicas
dc.subjectTrypanosoma cruzi
dc.subjectHIV-Pis
dc.subjectMode of action
dc.subjectPhysiological alterations
dc.subjectHIV aspartyl peptidase inhibitors
dc.titlePrimary evidence of the mechanisms of action of HIV aspartyl peptidase inhibitors on Trypanosoma cruzi trypomastigote forms
dc.typeArticle


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