PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum

Detalhes bibliográficos
Autor(a) principal: Machado, Patrícia de Almeida
Data de Publicação: 2021
Outros Autores: Gomes, Pollyanna Stephanie, Midlej, Vitor, Coimbra, Elaine Soares, Guedes, Herbert Leonel de Matos
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/46881
Resumo: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Universidade Federal de Juiz de Fora. Instituto de Ciências Biológicas. Juiz de Fora, MG, Brasil.
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spelling Machado, Patrícia de AlmeidaGomes, Pollyanna StephanieMidlej, VitorCoimbra, Elaine SoaresGuedes, Herbert Leonel de Matos2021-04-25T19:38:52Z2021-04-25T19:38:52Z2021MACHADO, Patrícia de Almeida et al. PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum. Frontiers in Microbiology, v. 12, p. 1-17, Jan. 2021.1664-302Xhttps://www.arca.fiocruz.br/handle/icict/4688110.3389/fmicb.2021.583834engFrontiers MediaLeishmaniose visceralQuimioterapia de leishmanioseProtease serinaSubtilisinaPF-429242Visceral leishmaniasisLeishmaniasis chemotherapySerine proteaseSubtilisinPF-429242PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantuminfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Universidade Federal de Juiz de Fora. Instituto de Ciências Biológicas. Juiz de Fora, MG, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.Universidade Federal de Juiz de Fora. Instituto de Ciências Biológicas. Núcleo de Pesquisa em Parasitologia. Juiz de Fora, MG, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. UFRJ Campus Duque de Caxias Professor Geraldo Cidade. Duque de Caxias, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Goes. Rio de Janeiro, RJ, Brasil.PF-429242 is an inhibitor of subtilisin, an important protease found in Leishmania. However, studies regarding the effect of PF-429242 on Leishmania are scarce. In this work we evaluated the antileishmanial effect of PF-429242 against Leishmania infantum and the mechanism involved in the death of the parasite. PF-429242 had low toxicity against mammalian cells (peritoneal macrophages) (CC50 = 189.07 µM) and presented activity against L. infantum promastigotes (IC50 = 2.78 µM) and intracellular amastigotes (IC50 = 14.07 µM), indicating selectivity toward the parasite. Transmission electron microscopy (TEM), as well as staining of L. infantum promastigotes with MitoTracker R Red, rhodamine 123 and MitoSOX, revealed that the mitochondria was a potential target of PF-429242. In addition, PF-429242 caused an accumulation of neutral lipids in promastigotes, which was demonstrated by Nile Red staining and TEM, and induced oxidative stress (H2DCFDA staining). Furthermore the formation of autophagic vacuoles in L. infantum promastigotes was observed by MDC staining and TEM. However, the killing induced by PF-429242 in L. infantum promastigotes appeared to be unrelated to apoptosis and/or necrosis as there was no phosphatidylserine externalization, DNA fragmentation or alterations in the permeability of the parasite plasma membrane, as assessed by annexin V-FITC, TUNEL and propidium iodide staining, respectively. The morphological and ultrastructural evaluation of the promastigotes by optical microscopy, scanning electron microscopy (SEM) and TEM, revealed the presence of parasites with flagellar defects. TEM analysis of the intracellular amastigotes indicated that mitochondrial damage and autophagy could also be involved in the death of these forms after treatment with PF-429242. In addition, PF-429242 treatment stimulated NO production from infected macrophage, but only at a high concentration (100 µM), as well as an increase of TNF levels after treatment with 10 µM of PF-429242. The compound did not stimulate ROS or IL-10 production. Together, these data highlight the antileishmanial potential of PF-429242, inducing several cellular alterations in the parasite, such as mitochondrial damage, neutral lipids accumulation, oxidative stress and autophagy which culminate in the death of L. infantum, as well as modulating host cellular responses that favor the development of an immune response against the parasite.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; 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dc.title.pt_BR.fl_str_mv PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum
title PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum
spellingShingle PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum
Machado, Patrícia de Almeida
Leishmaniose visceral
Quimioterapia de leishmaniose
Protease serina
Subtilisina
PF-429242
Visceral leishmaniasis
Leishmaniasis chemotherapy
Serine protease
Subtilisin
PF-429242
title_short PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum
title_full PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum
title_fullStr PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum
title_full_unstemmed PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum
title_sort PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum
author Machado, Patrícia de Almeida
author_facet Machado, Patrícia de Almeida
Gomes, Pollyanna Stephanie
Midlej, Vitor
Coimbra, Elaine Soares
Guedes, Herbert Leonel de Matos
author_role author
author2 Gomes, Pollyanna Stephanie
Midlej, Vitor
Coimbra, Elaine Soares
Guedes, Herbert Leonel de Matos
author2_role author
author
author
author
dc.contributor.author.fl_str_mv Machado, Patrícia de Almeida
Gomes, Pollyanna Stephanie
Midlej, Vitor
Coimbra, Elaine Soares
Guedes, Herbert Leonel de Matos
dc.subject.other.pt_BR.fl_str_mv Leishmaniose visceral
Quimioterapia de leishmaniose
Protease serina
Subtilisina
PF-429242
topic Leishmaniose visceral
Quimioterapia de leishmaniose
Protease serina
Subtilisina
PF-429242
Visceral leishmaniasis
Leishmaniasis chemotherapy
Serine protease
Subtilisin
PF-429242
dc.subject.en.pt_BR.fl_str_mv Visceral leishmaniasis
Leishmaniasis chemotherapy
Serine protease
Subtilisin
PF-429242
description Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório Interdisciplinar de Pesquisas Médicas. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Universidade Federal de Juiz de Fora. Instituto de Ciências Biológicas. Juiz de Fora, MG, Brasil.
publishDate 2021
dc.date.accessioned.fl_str_mv 2021-04-25T19:38:52Z
dc.date.available.fl_str_mv 2021-04-25T19:38:52Z
dc.date.issued.fl_str_mv 2021
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv MACHADO, Patrícia de Almeida et al. PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum. Frontiers in Microbiology, v. 12, p. 1-17, Jan. 2021.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/46881
dc.identifier.issn.pt_BR.fl_str_mv 1664-302X
dc.identifier.doi.none.fl_str_mv 10.3389/fmicb.2021.583834
identifier_str_mv MACHADO, Patrícia de Almeida et al. PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum. Frontiers in Microbiology, v. 12, p. 1-17, Jan. 2021.
1664-302X
10.3389/fmicb.2021.583834
url https://www.arca.fiocruz.br/handle/icict/46881
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
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collection Repositório Institucional da FIOCRUZ (ARCA)
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