Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/18207
Title: HIV aspartic peptidase inhibitors are effective drugs against the trypomastigote form of the human pathogen Trypanosoma cruzi
Authors: Sangenito, Leandro S.
Gonçalves, Diego S.
Seabra, Sergio H.
d`Avila-Levy, Claudia M.
Santos, André L. S.
Branquinha, Marta H.
Affilliation: Universidade Federal do Rio de Janeiro, Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Investigação de Peptidases. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro, Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Investigação de Peptidases. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro, Instituto de Química. Programa de Pós-Graduação em Bioquímica. Rio de Janeiro, RJ, Brasil.
Centro Universitário Estadual da Zona Oeste. Laboratório de Tecnologia em Cultura de Células. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Estudos Integrados em Protozoologia. Rio de Janeiro, RJ. Brasil.
Universidade Federal do Rio de Janeiro, Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Investigação de Peptidases. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro, Instituto de Química. Programa de Pós-Graduação em Bioquímica. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro, Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Investigação de Peptidases. Rio de Janeiro, RJ, Brasil.
Abstract: There is a general lack of effective and non-toxic chemotherapeutic agents against Chagas' disease despite more than a century of research. In this regard, we have verified the impact of human immunodeficiency virus aspartic peptidase inhibitors (HIV-PIs) on the viability and morphology of infective trypomastigote forms of Trypanosoma cruzi as well as on the aspartic peptidase and proteasome activities produced by this parasite. The effects of HIV-PIs on viability were assessed by counting motile parasites in a Neubauer chamber. Morphological alterations were detected by light microscopy of Giemsa-stained smears and scanning electron microscopy. Modulation of aspartic peptidase and proteasome activities by the HIV-PIs was measured by cleavage of fluorogenic peptide substrates. The majority of the HIV-PIs (6/9) were able to drastically decrease the viability of trypomastigotes after 4 h of treatment, with nelfinavir and lopinavir being the most effective compounds presenting LD50 values of 8.6 µM and 10.6 µM, respectively. Additionally, both HIV-PIs were demonstrated to be effective in a time- and cell density-dependent manner. Treatment with nelfinavir and lopinavir caused many morphological/ultrastructural alterations in trypomastigotes; parasites became round in shape, with reduced cell size and flagellar shortening. Nelfinavir and lopinavir were also capable of significantly inhibiting the aspartic peptidase and proteasome activities measured in trypomastigote extracts. These results strengthen the data on the positive effects of HIV-PIs on parasitic infections, possibly by targeting the parasite aspartic peptidase(s) and proteasome(s), opening a new possibility for the use of these clinically approved drugs as an alternative chemotherapy to treat Chagas' disease.
Keywords: Trypanosoma cruzi
HIV peptidase inhibitor
Aspartic peptidase
Proteasome
Morphological alterations
keywords: Trypanosoma cruzi
Inibidores de Proteases
HIV
Proteassoma
Alterações morfológicas
Issue Date: 2016
Publisher: Elsevier
Citation: SANGENITO, Leandro S. et al. HIV aspartic peptidase inhibitors are effective drugs against the trypomastigote form of the human pathogen Trypanosoma cruzi. International Journal of Antimicrobial Agents, v.48, p.440–444, 2016.
DOI: 10.1016/j.ijantimicag.2016.06.024
ISSN: 0924-8579
Copyright: restricted access
Appears in Collections:IOC - Artigos de Periódicos

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