Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection

Autores
Svagzdys, Ailin; Vilchez Larrea, Salomé Catalina; Alberca, Lucas Nicolás; Caram, Franco; Talevi, Alan; Fernandez Villamil, Silvia Hebe
Año de publicación
2019
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Poly-ADP-ribose polymer signaling is common to various nuclear processes related to DNA metabolism. As a reversible modification, it is regulated by a delicate balance of synthesis and degradation, being poly(ADP-ribose)glycohydrolase (PARG) the major hydrolase. We have demonstrated in mammalian cells that PARG inhibition or silencing is essential for the successful infection by the T. cruzi, making them an interesting target for the search of new treatments for Chagas disease. T. cruzi PARG inhibition also causes a delay in cell cycle. We have compiled a database of molecules tested against human PARG from which, we have inferred 1000 ligand-based classificatory models capable of recognizing hPARG inhibitors using a semicorrelation approach and a random subspace approximation. We have generated a ligand-based model ensemble capable of recognizing human PARG inhibitors, with excellent behavior in the in silico validation step. The ensemble was applied in VS campaign, finding 26 drugs that could potentially behave as PARG inhibitors. Six drugs were chosen based on their solubility and availability and were tested both on infected cells and T. cruzi epimastigote. We analyzed the infection in Vero cells using trypomastigotes expressing β-gal at 96 h PI. At 50 μM, Bromhexine and Rosuvastatine caused a marked reduction on the infection (96% and 55% compared to DMSO infection), while Sulfazalasine and Doxycycline led to a mild reduction in the infection (20% for both drugs). At the indicated concentration, these drugs did not affect host cell growth significantly. When tested on epimastigotes, only Doxycycline demonstrated to affect viability at concentrations ranging from 50-500 μM. These results indicate that while Bromhexine, Rosuvastatine and Sulfazalasine might modulate the infection by affecting the host cell PARG, Doxycycline could possibly be affecting both the parasite and the host cell enzyme, although effects on other molecular targets can not be disregarded.
Fil: Svagzdys, Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Caram, Franco. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fernandez Villamil, Silvia Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Asociación Argentina de Farmacología Experimental
Sociedad Argentina de Biología
Sociedad Argentina de Protozoología
Asociación Argentina de Nanomedicinas
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
The Histochemical Society
Materia
PARG
Inhibitors
Drug Repositioning
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/233996
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/233996
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network_name_str CONICET Digital (CONICET)
spelling Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infectionSvagzdys, AilinVilchez Larrea, Salomé CatalinaAlberca, Lucas NicolásCaram, FrancoTalevi, AlanFernandez Villamil, Silvia HebePARGInhibitorsDrug Repositioninghttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Poly-ADP-ribose polymer signaling is common to various nuclear processes related to DNA metabolism. As a reversible modification, it is regulated by a delicate balance of synthesis and degradation, being poly(ADP-ribose)glycohydrolase (PARG) the major hydrolase. We have demonstrated in mammalian cells that PARG inhibition or silencing is essential for the successful infection by the T. cruzi, making them an interesting target for the search of new treatments for Chagas disease. T. cruzi PARG inhibition also causes a delay in cell cycle. We have compiled a database of molecules tested against human PARG from which, we have inferred 1000 ligand-based classificatory models capable of recognizing hPARG inhibitors using a semicorrelation approach and a random subspace approximation. We have generated a ligand-based model ensemble capable of recognizing human PARG inhibitors, with excellent behavior in the in silico validation step. The ensemble was applied in VS campaign, finding 26 drugs that could potentially behave as PARG inhibitors. Six drugs were chosen based on their solubility and availability and were tested both on infected cells and T. cruzi epimastigote. We analyzed the infection in Vero cells using trypomastigotes expressing β-gal at 96 h PI. At 50 μM, Bromhexine and Rosuvastatine caused a marked reduction on the infection (96% and 55% compared to DMSO infection), while Sulfazalasine and Doxycycline led to a mild reduction in the infection (20% for both drugs). At the indicated concentration, these drugs did not affect host cell growth significantly. When tested on epimastigotes, only Doxycycline demonstrated to affect viability at concentrations ranging from 50-500 μM. These results indicate that while Bromhexine, Rosuvastatine and Sulfazalasine might modulate the infection by affecting the host cell PARG, Doxycycline could possibly be affecting both the parasite and the host cell enzyme, although effects on other molecular targets can not be disregarded.Fil: Svagzdys, Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Caram, Franco. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernandez Villamil, Silvia Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaLXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de LaboratorioMar del PlataArgentinaSociedad Argentina de Investigación ClínicaAsociación Argentina de Farmacología ExperimentalSociedad Argentina de BiologíaSociedad Argentina de ProtozoologíaAsociación Argentina de NanomedicinasAsociación Argentina de Ciencia y Tecnología de Animales de LaboratorioThe Histochemical SocietyFundación Revista Medicina2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/233996Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio; Mar del Plata; Argentina; 2019; 1-30025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://medicinabuenosaires.com/revistas/vol79-19/s4/vol79_s4.pdfInternacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:01:12Zoai:ri.conicet.gov.ar:11336/233996instacron: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:34982025-09-10 13:01:12.674CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection
title Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection
spellingShingle Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection
Svagzdys, Ailin
PARG
Inhibitors
Drug Repositioning
title_short Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection
title_full Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection
title_fullStr Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection
title_full_unstemmed Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection
title_sort Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection
dc.creator.none.fl_str_mv Svagzdys, Ailin
Vilchez Larrea, Salomé Catalina
Alberca, Lucas Nicolás
Caram, Franco
Talevi, Alan
Fernandez Villamil, Silvia Hebe
author Svagzdys, Ailin
author_facet Svagzdys, Ailin
Vilchez Larrea, Salomé Catalina
Alberca, Lucas Nicolás
Caram, Franco
Talevi, Alan
Fernandez Villamil, Silvia Hebe
author_role author
author2 Vilchez Larrea, Salomé Catalina
Alberca, Lucas Nicolás
Caram, Franco
Talevi, Alan
Fernandez Villamil, Silvia Hebe
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv PARG
Inhibitors
Drug Repositioning
topic PARG
Inhibitors
Drug Repositioning
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Poly-ADP-ribose polymer signaling is common to various nuclear processes related to DNA metabolism. As a reversible modification, it is regulated by a delicate balance of synthesis and degradation, being poly(ADP-ribose)glycohydrolase (PARG) the major hydrolase. We have demonstrated in mammalian cells that PARG inhibition or silencing is essential for the successful infection by the T. cruzi, making them an interesting target for the search of new treatments for Chagas disease. T. cruzi PARG inhibition also causes a delay in cell cycle. We have compiled a database of molecules tested against human PARG from which, we have inferred 1000 ligand-based classificatory models capable of recognizing hPARG inhibitors using a semicorrelation approach and a random subspace approximation. We have generated a ligand-based model ensemble capable of recognizing human PARG inhibitors, with excellent behavior in the in silico validation step. The ensemble was applied in VS campaign, finding 26 drugs that could potentially behave as PARG inhibitors. Six drugs were chosen based on their solubility and availability and were tested both on infected cells and T. cruzi epimastigote. We analyzed the infection in Vero cells using trypomastigotes expressing β-gal at 96 h PI. At 50 μM, Bromhexine and Rosuvastatine caused a marked reduction on the infection (96% and 55% compared to DMSO infection), while Sulfazalasine and Doxycycline led to a mild reduction in the infection (20% for both drugs). At the indicated concentration, these drugs did not affect host cell growth significantly. When tested on epimastigotes, only Doxycycline demonstrated to affect viability at concentrations ranging from 50-500 μM. These results indicate that while Bromhexine, Rosuvastatine and Sulfazalasine might modulate the infection by affecting the host cell PARG, Doxycycline could possibly be affecting both the parasite and the host cell enzyme, although effects on other molecular targets can not be disregarded.
Fil: Svagzdys, Ailin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Caram, Franco. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fernandez Villamil, Silvia Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Asociación Argentina de Farmacología Experimental
Sociedad Argentina de Biología
Sociedad Argentina de Protozoología
Asociación Argentina de Nanomedicinas
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
The Histochemical Society
description Poly-ADP-ribose polymer signaling is common to various nuclear processes related to DNA metabolism. As a reversible modification, it is regulated by a delicate balance of synthesis and degradation, being poly(ADP-ribose)glycohydrolase (PARG) the major hydrolase. We have demonstrated in mammalian cells that PARG inhibition or silencing is essential for the successful infection by the T. cruzi, making them an interesting target for the search of new treatments for Chagas disease. T. cruzi PARG inhibition also causes a delay in cell cycle. We have compiled a database of molecules tested against human PARG from which, we have inferred 1000 ligand-based classificatory models capable of recognizing hPARG inhibitors using a semicorrelation approach and a random subspace approximation. We have generated a ligand-based model ensemble capable of recognizing human PARG inhibitors, with excellent behavior in the in silico validation step. The ensemble was applied in VS campaign, finding 26 drugs that could potentially behave as PARG inhibitors. Six drugs were chosen based on their solubility and availability and were tested both on infected cells and T. cruzi epimastigote. We analyzed the infection in Vero cells using trypomastigotes expressing β-gal at 96 h PI. At 50 μM, Bromhexine and Rosuvastatine caused a marked reduction on the infection (96% and 55% compared to DMSO infection), while Sulfazalasine and Doxycycline led to a mild reduction in the infection (20% for both drugs). At the indicated concentration, these drugs did not affect host cell growth significantly. When tested on epimastigotes, only Doxycycline demonstrated to affect viability at concentrations ranging from 50-500 μM. These results indicate that while Bromhexine, Rosuvastatine and Sulfazalasine might modulate the infection by affecting the host cell PARG, Doxycycline could possibly be affecting both the parasite and the host cell enzyme, although effects on other molecular targets can not be disregarded.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
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http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/233996
Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio; Mar del Plata; Argentina; 2019; 1-3
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/233996
identifier_str_mv Effect of putative PARG inhibitors identified by an in silico approach on Trypanosoma cruzi infection; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio; Mar del Plata; Argentina; 2019; 1-3
0025-7680
1669-9106
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
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