Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-Methylaplysinopsin
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1021/acsomega.2c03395 http://hdl.handle.net/11449/241698 |
Resumo: | Chagas disease, caused by Trypanosoma cruzi, affects seven million people worldwide and lacks effective treatments. Using bioactivity-guided fractionation, NMR, and electrospray ionization-high resolution mass spectrometry (ESI-HRMS) spectral analysis, the indole alkaloid 6-bromo-2′-de-N-methylaplysinopsin (BMA) was isolated and chemically characterized from the marine coral Tubastraea tagusensis. BMA was tested against trypomastigotes and intracellular amastigotes of T. cruzi, resulting in IC50 values of 62 and 5.7 μM, respectively, with no mammalian cytotoxicity. The mechanism of action studies showed that BMA induced no alterations in the plasma membrane permeability but caused depolarization of the mitochondrial membrane potential, reducing ATP levels. Intracellular calcium levels were also reduced after the treatment, which was associated with pH alteration of acidocalcisomes. Using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)/MS analysis, alterations of mass spectral signals were observed after treatment with BMA, suggesting a different mechanism from benznidazole. In silico pharmacokinetic-pharmacodynamic (PKPD) parameters suggested a drug-likeness property, supporting the promising usefulness of this compound as a new hit for optimizations. |
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Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-MethylaplysinopsinChagas disease, caused by Trypanosoma cruzi, affects seven million people worldwide and lacks effective treatments. Using bioactivity-guided fractionation, NMR, and electrospray ionization-high resolution mass spectrometry (ESI-HRMS) spectral analysis, the indole alkaloid 6-bromo-2′-de-N-methylaplysinopsin (BMA) was isolated and chemically characterized from the marine coral Tubastraea tagusensis. BMA was tested against trypomastigotes and intracellular amastigotes of T. cruzi, resulting in IC50 values of 62 and 5.7 μM, respectively, with no mammalian cytotoxicity. The mechanism of action studies showed that BMA induced no alterations in the plasma membrane permeability but caused depolarization of the mitochondrial membrane potential, reducing ATP levels. Intracellular calcium levels were also reduced after the treatment, which was associated with pH alteration of acidocalcisomes. Using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)/MS analysis, alterations of mass spectral signals were observed after treatment with BMA, suggesting a different mechanism from benznidazole. In silico pharmacokinetic-pharmacodynamic (PKPD) parameters suggested a drug-likeness property, supporting the promising usefulness of this compound as a new hit for optimizations.Centre for Parasitology and Mycology Adolfo Lutz Institute, Av Dr Arnaldo 351, SPCentre of Natural Sciences and Humanities Federal University of ABC (UFABC), Avenida dos Estados 5001, SPDepartment of Organic Contaminants Instituto Adolfo Lutz, Av Dr Arnaldo 355, SPDepartment of Chemistry and Environmental Sciences Institute of Biosciences Humanities and Exact Sciences Universidade Estadual Paulista, R. Cristóvão Colombo 2265, SPCentre for Marine Biology Universidade de São Paulo, Rodovia Manoel Hypólito do Rego, Km 131, São Sebastião, SPDepartment of Chemistry and Environmental Sciences Institute of Biosciences Humanities and Exact Sciences Universidade Estadual Paulista, R. Cristóvão Colombo 2265, SPAdolfo Lutz InstituteUniversidade Federal do ABC (UFABC)Instituto Adolfo LutzUniversidade Estadual Paulista (UNESP)Universidade de São Paulo (USP)Romanelli, Maiara M.Amaral, MaiaraThevenard, FernandaSanta Cruz, Lucas M.Regasini, Luis O. [UNESP]Migotto, Alvaro E.Lago, João Henrique G.Tempone, Andre G.2023-03-01T21:17:18Z2023-03-01T21:17:18Z2022-08-16info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article28561-28570http://dx.doi.org/10.1021/acsomega.2c03395ACS Omega, v. 7, n. 32, p. 28561-28570, 2022.2470-1343http://hdl.handle.net/11449/24169810.1021/acsomega.2c033952-s2.0-85135993797Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengACS Omegainfo:eu-repo/semantics/openAccess2023-03-01T21:17:18Zoai:repositorio.unesp.br:11449/241698Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T14:18:54.223484Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-Methylaplysinopsin |
title |
Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-Methylaplysinopsin |
spellingShingle |
Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-Methylaplysinopsin Romanelli, Maiara M. |
title_short |
Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-Methylaplysinopsin |
title_full |
Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-Methylaplysinopsin |
title_fullStr |
Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-Methylaplysinopsin |
title_full_unstemmed |
Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-Methylaplysinopsin |
title_sort |
Mitochondrial Imbalance of Trypanosoma cruzi Induced by the Marine Alkaloid 6-Bromo-2′-de- N-Methylaplysinopsin |
author |
Romanelli, Maiara M. |
author_facet |
Romanelli, Maiara M. Amaral, Maiara Thevenard, Fernanda Santa Cruz, Lucas M. Regasini, Luis O. [UNESP] Migotto, Alvaro E. Lago, João Henrique G. Tempone, Andre G. |
author_role |
author |
author2 |
Amaral, Maiara Thevenard, Fernanda Santa Cruz, Lucas M. Regasini, Luis O. [UNESP] Migotto, Alvaro E. Lago, João Henrique G. Tempone, Andre G. |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Adolfo Lutz Institute Universidade Federal do ABC (UFABC) Instituto Adolfo Lutz Universidade Estadual Paulista (UNESP) Universidade de São Paulo (USP) |
dc.contributor.author.fl_str_mv |
Romanelli, Maiara M. Amaral, Maiara Thevenard, Fernanda Santa Cruz, Lucas M. Regasini, Luis O. [UNESP] Migotto, Alvaro E. Lago, João Henrique G. Tempone, Andre G. |
description |
Chagas disease, caused by Trypanosoma cruzi, affects seven million people worldwide and lacks effective treatments. Using bioactivity-guided fractionation, NMR, and electrospray ionization-high resolution mass spectrometry (ESI-HRMS) spectral analysis, the indole alkaloid 6-bromo-2′-de-N-methylaplysinopsin (BMA) was isolated and chemically characterized from the marine coral Tubastraea tagusensis. BMA was tested against trypomastigotes and intracellular amastigotes of T. cruzi, resulting in IC50 values of 62 and 5.7 μM, respectively, with no mammalian cytotoxicity. The mechanism of action studies showed that BMA induced no alterations in the plasma membrane permeability but caused depolarization of the mitochondrial membrane potential, reducing ATP levels. Intracellular calcium levels were also reduced after the treatment, which was associated with pH alteration of acidocalcisomes. Using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)/MS analysis, alterations of mass spectral signals were observed after treatment with BMA, suggesting a different mechanism from benznidazole. In silico pharmacokinetic-pharmacodynamic (PKPD) parameters suggested a drug-likeness property, supporting the promising usefulness of this compound as a new hit for optimizations. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-08-16 2023-03-01T21:17:18Z 2023-03-01T21:17:18Z |
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.uri.fl_str_mv |
http://dx.doi.org/10.1021/acsomega.2c03395 ACS Omega, v. 7, n. 32, p. 28561-28570, 2022. 2470-1343 http://hdl.handle.net/11449/241698 10.1021/acsomega.2c03395 2-s2.0-85135993797 |
url |
http://dx.doi.org/10.1021/acsomega.2c03395 http://hdl.handle.net/11449/241698 |
identifier_str_mv |
ACS Omega, v. 7, n. 32, p. 28561-28570, 2022. 2470-1343 10.1021/acsomega.2c03395 2-s2.0-85135993797 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
ACS Omega |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
28561-28570 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1808128345968214016 |