Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery
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/10.1371/journal.pone.0275002 http://hdl.handle.net/11449/247727 |
Resumo: | Investigating the chemical diversity of natural products from tropical environments is an inspiring approach to developing new drug candidates for neglected tropical diseases (NTDs). In the present study, phenotypic screenings for antiprotozoal activity and a combination of computational and biological approaches enabled the identification and characterization of four cytochalasins, which are fungal metabolites from Brazilian biodiversity sources. Cytochalasins A-D exhibited IC50 values ranging from 2 to 20 μM against intracellular Trypanosoma cruzi and Leishmania infantum amastigotes, values comparable to those of the standard drugs benznidazole and miltefosine for Chagas disease and leishmaniasis, respectively. Furthermore, cytochalasins A-D reduced L. infantum infections by more than 80% in THP-1 cells, most likely due to the inhibition of phagocytosis by interactions with actin. Molecular modelling studies have provided useful insights into the mechanism of action of this class of compounds. Furthermore, cytochalasins A-D showed moderate cytotoxicity against normal cell lines (HFF-1, THP-1, and HepG2) and a good overall profile for oral bioavailability assessed in vitro. The results of this study support the use of natural products from Brazilian biodiversity sources to find potential drug candidates for two of the most important NTDs. |
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Identification of natural cytochalasins as leads for neglected tropical diseases drug discoveryInvestigating the chemical diversity of natural products from tropical environments is an inspiring approach to developing new drug candidates for neglected tropical diseases (NTDs). In the present study, phenotypic screenings for antiprotozoal activity and a combination of computational and biological approaches enabled the identification and characterization of four cytochalasins, which are fungal metabolites from Brazilian biodiversity sources. Cytochalasins A-D exhibited IC50 values ranging from 2 to 20 μM against intracellular Trypanosoma cruzi and Leishmania infantum amastigotes, values comparable to those of the standard drugs benznidazole and miltefosine for Chagas disease and leishmaniasis, respectively. Furthermore, cytochalasins A-D reduced L. infantum infections by more than 80% in THP-1 cells, most likely due to the inhibition of phagocytosis by interactions with actin. Molecular modelling studies have provided useful insights into the mechanism of action of this class of compounds. Furthermore, cytochalasins A-D showed moderate cytotoxicity against normal cell lines (HFF-1, THP-1, and HepG2) and a good overall profile for oral bioavailability assessed in vitro. The results of this study support the use of natural products from Brazilian biodiversity sources to find potential drug candidates for two of the most important NTDs.Universidade Estadual PaulistaFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Laboratory of Medicinal and Computational Chemistry (LQMC) Centre for Research and Innovation in Biodiversity and Drug Discovery (CIBFar) São Carlos Institute of Physics (IFSC) University of São Paulo (USP), SPNuclei of Bioassays Biosynthesis and Ecophysiology of Natural Products (NuBBE) Department of Organic Chemistry Institute of Chemistry São Paulo State University (UNESP), SPNuclei of Bioassays Biosynthesis and Ecophysiology of Natural Products (NuBBE) Department of Organic Chemistry Institute of Chemistry São Paulo State University (UNESP), SPFAPESP: 2013/ 07600-3Universidade de São Paulo (USP)Universidade Estadual Paulista (UNESP)Valli, MariliaSouza, Julia MedeirosChelucci, Rafael ConsolinBiasetto, Carolina Rabal [UNESP]Araujo, Angela Regina [UNESP]da Silva Bolzani, Vanderlan [UNESP]Andricopulo, Adriano Defini2023-07-29T13:24:09Z2023-07-29T13:24:09Z2022-10-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1371/journal.pone.0275002PLoS ONE, v. 17, n. 10 October, 2022.1932-6203http://hdl.handle.net/11449/24772710.1371/journal.pone.02750022-s2.0-85139570536Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengPLoS ONEinfo:eu-repo/semantics/openAccess2023-07-29T13:24:09Zoai:repositorio.unesp.br:11449/247727Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T20:01:57.058700Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery |
title |
Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery |
spellingShingle |
Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery Valli, Marilia |
title_short |
Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery |
title_full |
Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery |
title_fullStr |
Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery |
title_full_unstemmed |
Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery |
title_sort |
Identification of natural cytochalasins as leads for neglected tropical diseases drug discovery |
author |
Valli, Marilia |
author_facet |
Valli, Marilia Souza, Julia Medeiros Chelucci, Rafael Consolin Biasetto, Carolina Rabal [UNESP] Araujo, Angela Regina [UNESP] da Silva Bolzani, Vanderlan [UNESP] Andricopulo, Adriano Defini |
author_role |
author |
author2 |
Souza, Julia Medeiros Chelucci, Rafael Consolin Biasetto, Carolina Rabal [UNESP] Araujo, Angela Regina [UNESP] da Silva Bolzani, Vanderlan [UNESP] Andricopulo, Adriano Defini |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) Universidade Estadual Paulista (UNESP) |
dc.contributor.author.fl_str_mv |
Valli, Marilia Souza, Julia Medeiros Chelucci, Rafael Consolin Biasetto, Carolina Rabal [UNESP] Araujo, Angela Regina [UNESP] da Silva Bolzani, Vanderlan [UNESP] Andricopulo, Adriano Defini |
description |
Investigating the chemical diversity of natural products from tropical environments is an inspiring approach to developing new drug candidates for neglected tropical diseases (NTDs). In the present study, phenotypic screenings for antiprotozoal activity and a combination of computational and biological approaches enabled the identification and characterization of four cytochalasins, which are fungal metabolites from Brazilian biodiversity sources. Cytochalasins A-D exhibited IC50 values ranging from 2 to 20 μM against intracellular Trypanosoma cruzi and Leishmania infantum amastigotes, values comparable to those of the standard drugs benznidazole and miltefosine for Chagas disease and leishmaniasis, respectively. Furthermore, cytochalasins A-D reduced L. infantum infections by more than 80% in THP-1 cells, most likely due to the inhibition of phagocytosis by interactions with actin. Molecular modelling studies have provided useful insights into the mechanism of action of this class of compounds. Furthermore, cytochalasins A-D showed moderate cytotoxicity against normal cell lines (HFF-1, THP-1, and HepG2) and a good overall profile for oral bioavailability assessed in vitro. The results of this study support the use of natural products from Brazilian biodiversity sources to find potential drug candidates for two of the most important NTDs. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-10-01 2023-07-29T13:24:09Z 2023-07-29T13:24:09Z |
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/10.1371/journal.pone.0275002 PLoS ONE, v. 17, n. 10 October, 2022. 1932-6203 http://hdl.handle.net/11449/247727 10.1371/journal.pone.0275002 2-s2.0-85139570536 |
url |
http://dx.doi.org/10.1371/journal.pone.0275002 http://hdl.handle.net/11449/247727 |
identifier_str_mv |
PLoS ONE, v. 17, n. 10 October, 2022. 1932-6203 10.1371/journal.pone.0275002 2-s2.0-85139570536 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
PLoS ONE |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
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 |
|
_version_ |
1808129151784189952 |