The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs

Autores
Vaca, Hugo Rolando; Celentano, Ana M.; Toscanini, María Agustina; Heimburg, Tino; Ghazy, Ehab; Zeyen, Patrik; Hauser, Alexander Thomas; Oliveira, Guilherme; Elissondo, María Celina; Jung, Manfred; Sippl, Wolfgang; Camicia, Federico; Rosenzvit, Mara Cecilia
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti).Methodology/principal findings: Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them-entinostat, TH65, and TH92 -had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed.Conclusion, significance: The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.
Fil: Vaca, Hugo Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente; Argentina
Fil: Celentano, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología; Argentina
Fil: Toscanini, María Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Heimburg, Tino. No especifíca;
Fil: Ghazy, Ehab. No especifíca;
Fil: Zeyen, Patrik. No especifíca;
Fil: Hauser, Alexander Thomas. Albert Ludwigs University of Freiburg; Alemania
Fil: Oliveira, Guilherme. Instituto Tecnológico Vale.; Brasil
Fil: Elissondo, María Celina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente; Argentina
Fil: Jung, Manfred. Albert Ludwigs University of Freiburg; Alemania
Fil: Sippl, Wolfgang. No especifíca;
Fil: Camicia, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Materia
HISTONE DEACETYLASE
CESTODIASES
ECHINOCOCCUS
ECHINOCOCCOSIS
CYSTICERCOSIS
DRUG CANDIDATES
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:11336/155043
Acceder
id CONICETDig_a75392288753dea075d1a18ea754a529
oai_identifier_str oai:ri.conicet.gov.ar:11336/155043
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugsVaca, Hugo RolandoCelentano, Ana M.Toscanini, María AgustinaHeimburg, TinoGhazy, EhabZeyen, PatrikHauser, Alexander ThomasOliveira, GuilhermeElissondo, María CelinaJung, ManfredSippl, WolfgangCamicia, FedericoRosenzvit, Mara CeciliaHISTONE DEACETYLASECESTODIASESECHINOCOCCUSECHINOCOCCOSISCYSTICERCOSISDRUG CANDIDATEShttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Background: Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti).Methodology/principal findings: Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them-entinostat, TH65, and TH92 -had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed.Conclusion, significance: The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.Fil: Vaca, Hugo Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente; ArgentinaFil: Celentano, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología; ArgentinaFil: Toscanini, María Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Heimburg, Tino. No especifíca;Fil: Ghazy, Ehab. No especifíca;Fil: Zeyen, Patrik. No especifíca;Fil: Hauser, Alexander Thomas. Albert Ludwigs University of Freiburg; AlemaniaFil: Oliveira, Guilherme. Instituto Tecnológico Vale.; BrasilFil: Elissondo, María Celina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente; ArgentinaFil: Jung, Manfred. Albert Ludwigs University of Freiburg; AlemaniaFil: Sippl, Wolfgang. No especifíca;Fil: Camicia, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaPublic Library of Science2021-03-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/155043Vaca, Hugo Rolando; Celentano, Ana M.; Toscanini, María Agustina; Heimburg, Tino; Ghazy, Ehab; et al.; The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs; Public Library of Science; Neglected Tropical Diseases; 15; 3; 3-3-2021; 1-231935-2735CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0009226info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0009226info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:48:36Zoai:ri.conicet.gov.ar:11336/155043instacron: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:34982025-09-29 09:48:37.111CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs
title The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs
spellingShingle The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs
Vaca, Hugo Rolando
HISTONE DEACETYLASE
CESTODIASES
ECHINOCOCCUS
ECHINOCOCCOSIS
CYSTICERCOSIS
DRUG CANDIDATES
title_short The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs
title_full The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs
title_fullStr The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs
title_full_unstemmed The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs
title_sort The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs
dc.creator.none.fl_str_mv Vaca, Hugo Rolando
Celentano, Ana M.
Toscanini, María Agustina
Heimburg, Tino
Ghazy, Ehab
Zeyen, Patrik
Hauser, Alexander Thomas
Oliveira, Guilherme
Elissondo, María Celina
Jung, Manfred
Sippl, Wolfgang
Camicia, Federico
Rosenzvit, Mara Cecilia
author Vaca, Hugo Rolando
author_facet Vaca, Hugo Rolando
Celentano, Ana M.
Toscanini, María Agustina
Heimburg, Tino
Ghazy, Ehab
Zeyen, Patrik
Hauser, Alexander Thomas
Oliveira, Guilherme
Elissondo, María Celina
Jung, Manfred
Sippl, Wolfgang
Camicia, Federico
Rosenzvit, Mara Cecilia
author_role author
author2 Celentano, Ana M.
Toscanini, María Agustina
Heimburg, Tino
Ghazy, Ehab
Zeyen, Patrik
Hauser, Alexander Thomas
Oliveira, Guilherme
Elissondo, María Celina
Jung, Manfred
Sippl, Wolfgang
Camicia, Federico
Rosenzvit, Mara Cecilia
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv HISTONE DEACETYLASE
CESTODIASES
ECHINOCOCCUS
ECHINOCOCCOSIS
CYSTICERCOSIS
DRUG CANDIDATES
topic HISTONE DEACETYLASE
CESTODIASES
ECHINOCOCCUS
ECHINOCOCCOSIS
CYSTICERCOSIS
DRUG CANDIDATES
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti).Methodology/principal findings: Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them-entinostat, TH65, and TH92 -had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed.Conclusion, significance: The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.
Fil: Vaca, Hugo Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente; Argentina
Fil: Celentano, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología; Argentina
Fil: Toscanini, María Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Heimburg, Tino. No especifíca;
Fil: Ghazy, Ehab. No especifíca;
Fil: Zeyen, Patrik. No especifíca;
Fil: Hauser, Alexander Thomas. Albert Ludwigs University of Freiburg; Alemania
Fil: Oliveira, Guilherme. Instituto Tecnológico Vale.; Brasil
Fil: Elissondo, María Celina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente; Argentina
Fil: Jung, Manfred. Albert Ludwigs University of Freiburg; Alemania
Fil: Sippl, Wolfgang. No especifíca;
Fil: Camicia, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
description Background: Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti).Methodology/principal findings: Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them-entinostat, TH65, and TH92 -had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed.Conclusion, significance: The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.
publishDate 2021
dc.date.none.fl_str_mv 2021-03-03
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/11336/155043
Vaca, Hugo Rolando; Celentano, Ana M.; Toscanini, María Agustina; Heimburg, Tino; Ghazy, Ehab; et al.; The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs; Public Library of Science; Neglected Tropical Diseases; 15; 3; 3-3-2021; 1-23
1935-2735
CONICET Digital
CONICET
url http://hdl.handle.net/11336/155043
identifier_str_mv Vaca, Hugo Rolando; Celentano, Ana M.; Toscanini, María Agustina; Heimburg, Tino; Ghazy, Ehab; et al.; The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs; Public Library of Science; Neglected Tropical Diseases; 15; 3; 3-3-2021; 1-23
1935-2735
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0009226
info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pntd.0009226
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
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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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