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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/18345
Ver los metadatos del registro completo
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oai:ri.conicet.gov.ar:11336/18345 |
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3498 |
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CONICET Digital (CONICET) |
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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 Técnicas2025-09-03T10:01:52Zoai: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:34982025-09-03 10:01:52.818CONICET 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 |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1842269722634092544 |
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13.13397 |