Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity

Autores
Sant’Anna, Ricardo; Gallego, Pablo; Robinson, Lei Z.; Pereira Henriques, Alda; Ferreira, Nelson; Pinheiro, Francisca; Esperante, Sebastian; Pallares, Irantzu; Huertas, Oscar; Almeida, Maria Rosario; Reixach, Natalia; Insa, Raul; Velazquez Campoy, Adrian; Reverter, David; Reig, Nuria; Ventura, Salvador
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.
Fil: Sant’Anna, Ricardo. Universitat Autonoma de Barcelona; España
Fil: Gallego, Pablo. Universitat Autonoma de Barcelona; España
Fil: Robinson, Lei Z.. The Scripps Research Institute; Estados Unidos
Fil: Pereira Henriques, Alda. Universidad de Porto; Portugal
Fil: Ferreira, Nelson. Universidad de Porto; Portugal
Fil: Pinheiro, Francisca. Universitat Autonoma de Barcelona; España
Fil: Esperante, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad de Barcelona; España
Fil: Pallares, Irantzu. Universitat Autonoma de Barcelona; España
Fil: Huertas, Oscar. SOM-Biotech; España
Fil: Almeida, Maria Rosario. Universidad de Porto; Portugal
Fil: Reixach, Natalia. The Scripps Research Institute; Estados Unidos
Fil: Insa, Raul. SOM-Biotech; España
Fil: Velazquez Campoy, Adrian. Fundación ARAID; España. Universidad de Zaragoza; España. Instituto de Investigación Sanitaria de Aragón; España
Fil: Reverter, David. Universitat Autonoma de Barcelona; España
Fil: Reig, Nuria. SOM-Biotech; España
Fil: Ventura, Salvador. Universitat Autonoma de Barcelona; España
Materia
Amyloidogenesis
Tolcapone
Transthyretin
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:11336/18345
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/18345
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicitySant’Anna, RicardoGallego, PabloRobinson, Lei Z.Pereira Henriques, AldaFerreira, NelsonPinheiro, FranciscaEsperante, SebastianPallares, IrantzuHuertas, OscarAlmeida, Maria RosarioReixach, NataliaInsa, RaulVelazquez Campoy, AdrianReverter, DavidReig, NuriaVentura, SalvadorAmyloidogenesisTolcaponeTransthyretinRepositioninghttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.Fil: Sant’Anna, Ricardo. Universitat Autonoma de Barcelona; EspañaFil: Gallego, Pablo. Universitat Autonoma de Barcelona; EspañaFil: Robinson, Lei Z.. The Scripps Research Institute; Estados UnidosFil: Pereira Henriques, Alda. Universidad de Porto; PortugalFil: Ferreira, Nelson. Universidad de Porto; PortugalFil: Pinheiro, Francisca. Universitat Autonoma de Barcelona; EspañaFil: Esperante, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad de Barcelona; EspañaFil: Pallares, Irantzu. Universitat Autonoma de Barcelona; EspañaFil: Huertas, Oscar. SOM-Biotech; EspañaFil: Almeida, Maria Rosario. Universidad de Porto; PortugalFil: Reixach, Natalia. The Scripps Research Institute; Estados UnidosFil: Insa, Raul. SOM-Biotech; EspañaFil: Velazquez Campoy, Adrian. Fundación ARAID; España. Universidad de Zaragoza; España. Instituto de Investigación Sanitaria de Aragón; EspañaFil: Reverter, David. Universitat Autonoma de Barcelona; EspañaFil: Reig, Nuria. SOM-Biotech; EspañaFil: Ventura, Salvador. Universitat Autonoma de Barcelona; EspañaNature Publishing Group2016-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/18345Sant’Anna, Ricardo; Gallego, Pablo; Robinson, Lei Z.; Pereira Henriques, Alda; Ferreira, Nelson; et al.; Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity; Nature Publishing Group; Nature Communications; 7; 10787; 2-2016; 1-132041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/ncomms10787info:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms10787info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:16:28Zoai:ri.conicet.gov.ar:11336/18345instacron: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 10:16:28.327CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
title Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
spellingShingle Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
Sant’Anna, Ricardo
Amyloidogenesis
Tolcapone
Transthyretin
Repositioning
title_short Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
title_full Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
title_fullStr Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
title_full_unstemmed Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
title_sort Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
dc.creator.none.fl_str_mv Sant’Anna, Ricardo
Gallego, Pablo
Robinson, Lei Z.
Pereira Henriques, Alda
Ferreira, Nelson
Pinheiro, Francisca
Esperante, Sebastian
Pallares, Irantzu
Huertas, Oscar
Almeida, Maria Rosario
Reixach, Natalia
Insa, Raul
Velazquez Campoy, Adrian
Reverter, David
Reig, Nuria
Ventura, Salvador
author Sant’Anna, Ricardo
author_facet Sant’Anna, Ricardo
Gallego, Pablo
Robinson, Lei Z.
Pereira Henriques, Alda
Ferreira, Nelson
Pinheiro, Francisca
Esperante, Sebastian
Pallares, Irantzu
Huertas, Oscar
Almeida, Maria Rosario
Reixach, Natalia
Insa, Raul
Velazquez Campoy, Adrian
Reverter, David
Reig, Nuria
Ventura, Salvador
author_role author
author2 Gallego, Pablo
Robinson, Lei Z.
Pereira Henriques, Alda
Ferreira, Nelson
Pinheiro, Francisca
Esperante, Sebastian
Pallares, Irantzu
Huertas, Oscar
Almeida, Maria Rosario
Reixach, Natalia
Insa, Raul
Velazquez Campoy, Adrian
Reverter, David
Reig, Nuria
Ventura, Salvador
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Amyloidogenesis
Tolcapone
Transthyretin
Repositioning
topic Amyloidogenesis
Tolcapone
Transthyretin
Repositioning
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.4
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.
Fil: Sant’Anna, Ricardo. Universitat Autonoma de Barcelona; España
Fil: Gallego, Pablo. Universitat Autonoma de Barcelona; España
Fil: Robinson, Lei Z.. The Scripps Research Institute; Estados Unidos
Fil: Pereira Henriques, Alda. Universidad de Porto; Portugal
Fil: Ferreira, Nelson. Universidad de Porto; Portugal
Fil: Pinheiro, Francisca. Universitat Autonoma de Barcelona; España
Fil: Esperante, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad de Barcelona; España
Fil: Pallares, Irantzu. Universitat Autonoma de Barcelona; España
Fil: Huertas, Oscar. SOM-Biotech; España
Fil: Almeida, Maria Rosario. Universidad de Porto; Portugal
Fil: Reixach, Natalia. The Scripps Research Institute; Estados Unidos
Fil: Insa, Raul. SOM-Biotech; España
Fil: Velazquez Campoy, Adrian. Fundación ARAID; España. Universidad de Zaragoza; España. Instituto de Investigación Sanitaria de Aragón; España
Fil: Reverter, David. Universitat Autonoma de Barcelona; España
Fil: Reig, Nuria. SOM-Biotech; España
Fil: Ventura, Salvador. Universitat Autonoma de Barcelona; España
description Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.
publishDate 2016
dc.date.none.fl_str_mv 2016-02
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/11336/18345
Sant’Anna, Ricardo; Gallego, Pablo; Robinson, Lei Z.; Pereira Henriques, Alda; Ferreira, Nelson; et al.; Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity; Nature Publishing Group; Nature Communications; 7; 10787; 2-2016; 1-13
2041-1723
CONICET Digital
CONICET
url http://hdl.handle.net/11336/18345
identifier_str_mv Sant’Anna, Ricardo; Gallego, Pablo; Robinson, Lei Z.; Pereira Henriques, Alda; Ferreira, Nelson; et al.; Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity; Nature Publishing Group; Nature Communications; 7; 10787; 2-2016; 1-13
2041-1723
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.nature.com/articles/ncomms10787
info:eu-repo/semantics/altIdentifier/doi/10.1038/ncomms10787
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
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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 13.070432

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