Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing

Autores
Reigada, Chantal; Martínez Sayé, Melisa Soledad; Phanstiel, Otto; Valera Vera, Edward Augusto; Miranda, Mariana Reneé; Pereira, Claudio Alejandro
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Trypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In T. cruzi the transport of polyamines is essential because this organism is unable to synthesize these compounds de novo. Therefore, the uptake of polyamines from the extracellular medium is critical for survival of the parasite. The anthracene-putrescine conjugate Ant4 was first designed as a polyamine transport probe in cancer cells. Ant4 was also found to inhibit the polyamine transport system and produced a strong trypanocidal effect in T. cruzi. Considering that Ant4 is not currently approved by the FDA, in this work we performed computer simulations to find trypanocidal drugs approved for use in humans that have structures and activities similar to Ant4. Through a similarity ligand-based virtual screening using Ant4 as reference molecule, four possible inhibitors of polyamine transport were found. Three of them, promazine, chlorpromazine and clomipramine, showed to be effective inhibitors of putrescine uptake, and also revealed a trypanocidal activity in epimastigotes (IC50 values of 69.0, 50.8 and 49.4 μM, respectively) and trypomastigotes (IC50 values of 3.5, 2.8 and 1.4 μM, respectively). Finally, molecular docking simulations suggest that the interactions between the T. cruzi polyamine transporter TcPAT12 and all the identified inhibitors occur in the same region of the protein. However, this location is different from the site occupied by the natural substrates. The value of this effort is that repurposing known drugs in the treatment of other pathologies, especially neglected diseases such as Chagas disease, significantly decreases the time and economic cost of implementation.
Fil: Reigada, Chantal. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Martínez Sayé, Melisa Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Phanstiel, Otto. University Of Central Florida; Estados Unidos
Fil: Valera Vera, Edward Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Miranda, Mariana Reneé. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Pereira, Claudio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Materia
TRYPANOSOMA CRUZI
CHAGAS DISEASE
POLYAMINE TRANSPORT
DRUG REPOSITIONING
TRYPANOCIDAL DRUGS
POLYAMINES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/105176

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network_name_str CONICET Digital (CONICET)
spelling Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug RepurposingReigada, ChantalMartínez Sayé, Melisa SoledadPhanstiel, OttoValera Vera, Edward AugustoMiranda, Mariana ReneéPereira, Claudio AlejandroTRYPANOSOMA CRUZICHAGAS DISEASEPOLYAMINE TRANSPORTDRUG REPOSITIONINGTRYPANOCIDAL DRUGSPOLYAMINEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Trypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In T. cruzi the transport of polyamines is essential because this organism is unable to synthesize these compounds de novo. Therefore, the uptake of polyamines from the extracellular medium is critical for survival of the parasite. The anthracene-putrescine conjugate Ant4 was first designed as a polyamine transport probe in cancer cells. Ant4 was also found to inhibit the polyamine transport system and produced a strong trypanocidal effect in T. cruzi. Considering that Ant4 is not currently approved by the FDA, in this work we performed computer simulations to find trypanocidal drugs approved for use in humans that have structures and activities similar to Ant4. Through a similarity ligand-based virtual screening using Ant4 as reference molecule, four possible inhibitors of polyamine transport were found. Three of them, promazine, chlorpromazine and clomipramine, showed to be effective inhibitors of putrescine uptake, and also revealed a trypanocidal activity in epimastigotes (IC50 values of 69.0, 50.8 and 49.4 μM, respectively) and trypomastigotes (IC50 values of 3.5, 2.8 and 1.4 μM, respectively). Finally, molecular docking simulations suggest that the interactions between the T. cruzi polyamine transporter TcPAT12 and all the identified inhibitors occur in the same region of the protein. However, this location is different from the site occupied by the natural substrates. The value of this effort is that repurposing known drugs in the treatment of other pathologies, especially neglected diseases such as Chagas disease, significantly decreases the time and economic cost of implementation.Fil: Reigada, Chantal. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Martínez Sayé, Melisa Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Phanstiel, Otto. University Of Central Florida; Estados UnidosFil: Valera Vera, Edward Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Miranda, Mariana Reneé. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFil: Pereira, Claudio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; ArgentinaFrontiers Research Foundation2019-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/105176Reigada, Chantal; Martínez Sayé, Melisa Soledad; Phanstiel, Otto; Valera Vera, Edward Augusto; Miranda, Mariana Reneé; et al.; Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing; Frontiers Research Foundation; Frontiers in Medicine; 6; 10-2019; 1-82296-858XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.3389/fmed.2019.00256info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fmed.2019.00256/fullinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:51:29Zoai:ri.conicet.gov.ar:11336/105176instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:51:29.742CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing
title Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing
spellingShingle Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing
Reigada, Chantal
TRYPANOSOMA CRUZI
CHAGAS DISEASE
POLYAMINE TRANSPORT
DRUG REPOSITIONING
TRYPANOCIDAL DRUGS
POLYAMINES
title_short Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing
title_full Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing
title_fullStr Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing
title_full_unstemmed Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing
title_sort Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing
dc.creator.none.fl_str_mv Reigada, Chantal
Martínez Sayé, Melisa Soledad
Phanstiel, Otto
Valera Vera, Edward Augusto
Miranda, Mariana Reneé
Pereira, Claudio Alejandro
author Reigada, Chantal
author_facet Reigada, Chantal
Martínez Sayé, Melisa Soledad
Phanstiel, Otto
Valera Vera, Edward Augusto
Miranda, Mariana Reneé
Pereira, Claudio Alejandro
author_role author
author2 Martínez Sayé, Melisa Soledad
Phanstiel, Otto
Valera Vera, Edward Augusto
Miranda, Mariana Reneé
Pereira, Claudio Alejandro
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv TRYPANOSOMA CRUZI
CHAGAS DISEASE
POLYAMINE TRANSPORT
DRUG REPOSITIONING
TRYPANOCIDAL DRUGS
POLYAMINES
topic TRYPANOSOMA CRUZI
CHAGAS DISEASE
POLYAMINE TRANSPORT
DRUG REPOSITIONING
TRYPANOCIDAL DRUGS
POLYAMINES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Trypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In T. cruzi the transport of polyamines is essential because this organism is unable to synthesize these compounds de novo. Therefore, the uptake of polyamines from the extracellular medium is critical for survival of the parasite. The anthracene-putrescine conjugate Ant4 was first designed as a polyamine transport probe in cancer cells. Ant4 was also found to inhibit the polyamine transport system and produced a strong trypanocidal effect in T. cruzi. Considering that Ant4 is not currently approved by the FDA, in this work we performed computer simulations to find trypanocidal drugs approved for use in humans that have structures and activities similar to Ant4. Through a similarity ligand-based virtual screening using Ant4 as reference molecule, four possible inhibitors of polyamine transport were found. Three of them, promazine, chlorpromazine and clomipramine, showed to be effective inhibitors of putrescine uptake, and also revealed a trypanocidal activity in epimastigotes (IC50 values of 69.0, 50.8 and 49.4 μM, respectively) and trypomastigotes (IC50 values of 3.5, 2.8 and 1.4 μM, respectively). Finally, molecular docking simulations suggest that the interactions between the T. cruzi polyamine transporter TcPAT12 and all the identified inhibitors occur in the same region of the protein. However, this location is different from the site occupied by the natural substrates. The value of this effort is that repurposing known drugs in the treatment of other pathologies, especially neglected diseases such as Chagas disease, significantly decreases the time and economic cost of implementation.
Fil: Reigada, Chantal. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Martínez Sayé, Melisa Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Phanstiel, Otto. University Of Central Florida; Estados Unidos
Fil: Valera Vera, Edward Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Miranda, Mariana Reneé. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
Fil: Pereira, Claudio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
description Trypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In T. cruzi the transport of polyamines is essential because this organism is unable to synthesize these compounds de novo. Therefore, the uptake of polyamines from the extracellular medium is critical for survival of the parasite. The anthracene-putrescine conjugate Ant4 was first designed as a polyamine transport probe in cancer cells. Ant4 was also found to inhibit the polyamine transport system and produced a strong trypanocidal effect in T. cruzi. Considering that Ant4 is not currently approved by the FDA, in this work we performed computer simulations to find trypanocidal drugs approved for use in humans that have structures and activities similar to Ant4. Through a similarity ligand-based virtual screening using Ant4 as reference molecule, four possible inhibitors of polyamine transport were found. Three of them, promazine, chlorpromazine and clomipramine, showed to be effective inhibitors of putrescine uptake, and also revealed a trypanocidal activity in epimastigotes (IC50 values of 69.0, 50.8 and 49.4 μM, respectively) and trypomastigotes (IC50 values of 3.5, 2.8 and 1.4 μM, respectively). Finally, molecular docking simulations suggest that the interactions between the T. cruzi polyamine transporter TcPAT12 and all the identified inhibitors occur in the same region of the protein. However, this location is different from the site occupied by the natural substrates. The value of this effort is that repurposing known drugs in the treatment of other pathologies, especially neglected diseases such as Chagas disease, significantly decreases the time and economic cost of implementation.
publishDate 2019
dc.date.none.fl_str_mv 2019-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/105176
Reigada, Chantal; Martínez Sayé, Melisa Soledad; Phanstiel, Otto; Valera Vera, Edward Augusto; Miranda, Mariana Reneé; et al.; Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing; Frontiers Research Foundation; Frontiers in Medicine; 6; 10-2019; 1-8
2296-858X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/105176
identifier_str_mv Reigada, Chantal; Martínez Sayé, Melisa Soledad; Phanstiel, Otto; Valera Vera, Edward Augusto; Miranda, Mariana Reneé; et al.; Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing; Frontiers Research Foundation; Frontiers in Medicine; 6; 10-2019; 1-8
2296-858X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.3389/fmed.2019.00256
info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fmed.2019.00256/full
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Research Foundation
publisher.none.fl_str_mv Frontiers Research Foundation
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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