Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay

Autores
Tavernelli, Luis Emilio; Alonso, Victoria Lucia; Peña, Imanol; Rodríguez Araya, Elvio; Manarin, Romina; Cantizani, Juan; Martin, Julio; Salamanca, Juan; Bamborough, Paul; Calderón, Felix; Gabarro, Raquel; Serra, Esteban Carlos
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most proteins with bromodomains are part of nuclear complexes that interact with acetylated histone residues and regulate DNA replication, transcription, and repair through chromatin structure remodeling. Bromodomain inhibitors are small molecules that bind to the hydrophobic pocket of bromodomains, interfering with the interaction with acetylated histones. Using a fluorescent probe, we have developed an assay to select inhibitors of the bromodomain factor 2 of Trypanosoma cruzi (TcBDF2) using fluorescence polarization. Initially, a library of 28,251 compounds was screened in an endpoint assay. The top 350-ranked compounds were further analyzed in a dose-response assay. From this analysis, seven compounds were obtained that had not been previously characterized as bromodomain inhibitors. Although these compounds did not exhibit significant trypanocidal activity, all showed bona fide interaction with TcBDF2 with dissociation constants between 1 and 3 µM validating these assays to search for bromodomain inhibitors.
Fil: Tavernelli, Luis Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Alonso, Victoria Lucia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Peña, Imanol. Glaxosmithkline Global Health; España
Fil: Rodríguez Araya, Elvio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina
Fil: Manarin, Romina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina
Fil: Cantizani, Juan. Glaxosmithkline Global Health; España
Fil: Martin, Julio. Glaxosmithkline Global Health; España
Fil: Salamanca, Juan. Glaxosmithkline Global Health; España
Fil: Bamborough, Paul. No especifíca;
Fil: Calderón, Felix. Glaxosmithkline Global Health; España
Fil: Gabarro, Raquel. Glaxosmithkline Global Health; España
Fil: Serra, Esteban Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina
Materia
Trypanosoma cruzi
Bromodomain inhibitors
Drug screening
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:11336/266346
Acceder
id CONICETDig_e34dfe51434ec7f4c6ab885a84230fb8
oai_identifier_str oai:ri.conicet.gov.ar:11336/266346
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assayTavernelli, Luis EmilioAlonso, Victoria LuciaPeña, ImanolRodríguez Araya, ElvioManarin, RominaCantizani, JuanMartin, JulioSalamanca, JuanBamborough, PaulCalderón, FelixGabarro, RaquelSerra, Esteban CarlosTrypanosoma cruziBromodomain inhibitorsDrug screeninghttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most proteins with bromodomains are part of nuclear complexes that interact with acetylated histone residues and regulate DNA replication, transcription, and repair through chromatin structure remodeling. Bromodomain inhibitors are small molecules that bind to the hydrophobic pocket of bromodomains, interfering with the interaction with acetylated histones. Using a fluorescent probe, we have developed an assay to select inhibitors of the bromodomain factor 2 of Trypanosoma cruzi (TcBDF2) using fluorescence polarization. Initially, a library of 28,251 compounds was screened in an endpoint assay. The top 350-ranked compounds were further analyzed in a dose-response assay. From this analysis, seven compounds were obtained that had not been previously characterized as bromodomain inhibitors. Although these compounds did not exhibit significant trypanocidal activity, all showed bona fide interaction with TcBDF2 with dissociation constants between 1 and 3 µM validating these assays to search for bromodomain inhibitors.Fil: Tavernelli, Luis Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Alonso, Victoria Lucia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Peña, Imanol. Glaxosmithkline Global Health; EspañaFil: Rodríguez Araya, Elvio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; ArgentinaFil: Manarin, Romina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Cantizani, Juan. Glaxosmithkline Global Health; EspañaFil: Martin, Julio. Glaxosmithkline Global Health; EspañaFil: Salamanca, Juan. Glaxosmithkline Global Health; EspañaFil: Bamborough, Paul. No especifíca;Fil: Calderón, Felix. Glaxosmithkline Global Health; EspañaFil: Gabarro, Raquel. Glaxosmithkline Global Health; EspañaFil: Serra, Esteban Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; ArgentinaAmerican Society for Microbiology2024-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/266346Tavernelli, Luis Emilio; Alonso, Victoria Lucia; Peña, Imanol; Rodríguez Araya, Elvio; Manarin, Romina; et al.; Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 68; 8; 8-2024; 1-120066-4804CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/aac.00243-24info:eu-repo/semantics/altIdentifier/doi/10.1128/aac.00243-24info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:52:30Zoai:ri.conicet.gov.ar:11336/266346instacron: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:34982025-09-03 09:52:31.009CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay
title Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay
spellingShingle Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay
Tavernelli, Luis Emilio
Trypanosoma cruzi
Bromodomain inhibitors
Drug screening
title_short Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay
title_full Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay
title_fullStr Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay
title_full_unstemmed Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay
title_sort Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay
dc.creator.none.fl_str_mv Tavernelli, Luis Emilio
Alonso, Victoria Lucia
Peña, Imanol
Rodríguez Araya, Elvio
Manarin, Romina
Cantizani, Juan
Martin, Julio
Salamanca, Juan
Bamborough, Paul
Calderón, Felix
Gabarro, Raquel
Serra, Esteban Carlos
author Tavernelli, Luis Emilio
author_facet Tavernelli, Luis Emilio
Alonso, Victoria Lucia
Peña, Imanol
Rodríguez Araya, Elvio
Manarin, Romina
Cantizani, Juan
Martin, Julio
Salamanca, Juan
Bamborough, Paul
Calderón, Felix
Gabarro, Raquel
Serra, Esteban Carlos
author_role author
author2 Alonso, Victoria Lucia
Peña, Imanol
Rodríguez Araya, Elvio
Manarin, Romina
Cantizani, Juan
Martin, Julio
Salamanca, Juan
Bamborough, Paul
Calderón, Felix
Gabarro, Raquel
Serra, Esteban Carlos
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Trypanosoma cruzi
Bromodomain inhibitors
Drug screening
topic Trypanosoma cruzi
Bromodomain inhibitors
Drug screening
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most proteins with bromodomains are part of nuclear complexes that interact with acetylated histone residues and regulate DNA replication, transcription, and repair through chromatin structure remodeling. Bromodomain inhibitors are small molecules that bind to the hydrophobic pocket of bromodomains, interfering with the interaction with acetylated histones. Using a fluorescent probe, we have developed an assay to select inhibitors of the bromodomain factor 2 of Trypanosoma cruzi (TcBDF2) using fluorescence polarization. Initially, a library of 28,251 compounds was screened in an endpoint assay. The top 350-ranked compounds were further analyzed in a dose-response assay. From this analysis, seven compounds were obtained that had not been previously characterized as bromodomain inhibitors. Although these compounds did not exhibit significant trypanocidal activity, all showed bona fide interaction with TcBDF2 with dissociation constants between 1 and 3 µM validating these assays to search for bromodomain inhibitors.
Fil: Tavernelli, Luis Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Alonso, Victoria Lucia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Peña, Imanol. Glaxosmithkline Global Health; España
Fil: Rodríguez Araya, Elvio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina
Fil: Manarin, Romina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina
Fil: Cantizani, Juan. Glaxosmithkline Global Health; España
Fil: Martin, Julio. Glaxosmithkline Global Health; España
Fil: Salamanca, Juan. Glaxosmithkline Global Health; España
Fil: Bamborough, Paul. No especifíca;
Fil: Calderón, Felix. Glaxosmithkline Global Health; España
Fil: Gabarro, Raquel. Glaxosmithkline Global Health; España
Fil: Serra, Esteban Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas.; Argentina
description Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most proteins with bromodomains are part of nuclear complexes that interact with acetylated histone residues and regulate DNA replication, transcription, and repair through chromatin structure remodeling. Bromodomain inhibitors are small molecules that bind to the hydrophobic pocket of bromodomains, interfering with the interaction with acetylated histones. Using a fluorescent probe, we have developed an assay to select inhibitors of the bromodomain factor 2 of Trypanosoma cruzi (TcBDF2) using fluorescence polarization. Initially, a library of 28,251 compounds was screened in an endpoint assay. The top 350-ranked compounds were further analyzed in a dose-response assay. From this analysis, seven compounds were obtained that had not been previously characterized as bromodomain inhibitors. Although these compounds did not exhibit significant trypanocidal activity, all showed bona fide interaction with TcBDF2 with dissociation constants between 1 and 3 µM validating these assays to search for bromodomain inhibitors.
publishDate 2024
dc.date.none.fl_str_mv 2024-08
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/11336/266346
Tavernelli, Luis Emilio; Alonso, Victoria Lucia; Peña, Imanol; Rodríguez Araya, Elvio; Manarin, Romina; et al.; Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 68; 8; 8-2024; 1-12
0066-4804
CONICET Digital
CONICET
url http://hdl.handle.net/11336/266346
identifier_str_mv Tavernelli, Luis Emilio; Alonso, Victoria Lucia; Peña, Imanol; Rodríguez Araya, Elvio; Manarin, Romina; et al.; Identification of novel bromodomain inhibitors of Trypanosoma cruzi bromodomain factor 2 ( Tc BDF2) using a fluorescence polarization-based high-throughput assay; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 68; 8; 8-2024; 1-12
0066-4804
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.asm.org/doi/10.1128/aac.00243-24
info:eu-repo/semantics/altIdentifier/doi/10.1128/aac.00243-24
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
application/pdf
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
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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score 13.13397

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