Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis

Autores
Pinheiro, Francisca; Varejão, Nathalia; Esperante, Sebastian; Santos, Jaime; Velázquez-Campoy, Adrián; Reverter, David; Pallarès, Irantzu; Ventura, Salvador
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain. In addition, despite current pharmacological strategies have shown to be effective against in vivo TTR aggregation by stabilizing the tetramer native structure and precluding its dissociation, they display low brain permeability. Recently, we have repurposed tolcapone as a molecule to treat systemic ATTR. Crystal structures and biophysical analysis converge to demonstrate that tolcapone binds with high affinity and specificity to three unstable leptomeningeal TTR variants, stabilizing them and, consequently, inhibiting their aggregation. Because tolcapone is an FDA-approved drug that crosses the blood-brain barrier, our results suggest that it can translate into a first disease-modifying therapy for leptomeningeal amyloidosis.
Fil: Pinheiro, Francisca. Universitat Autònoma de Barcelona; España
Fil: Varejão, Nathalia. Universitat Autònoma de Barcelona; España
Fil: Esperante, Sebastian. Fundación para la Investigación en Infectología Infantil; Argentina. 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
Fil: Santos, Jaime. Universitat Autònoma de Barcelona; España
Fil: Velázquez-Campoy, Adrián. Universidad de Zaragoza; España. Aragon Institute for Health Research; España. Biomedical Research Network Center in Hepatic and Digestive Diseases; España
Fil: Reverter, David. Universitat Autònoma de Barcelona; España
Fil: Pallarès, Irantzu. Universitat Autònoma de Barcelona; España
Fil: Ventura, Salvador. Universitat Autònoma de Barcelona; España
Materia
AMYLOIDOSIS
CRYSTAL STRUCTURES
PROTEIN AGGREGATION
TOLCAPONE
TRANSTHYRETIN
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:11336/133306
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/133306
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosisPinheiro, FranciscaVarejão, NathaliaEsperante, SebastianSantos, JaimeVelázquez-Campoy, AdriánReverter, DavidPallarès, IrantzuVentura, SalvadorAMYLOIDOSISCRYSTAL STRUCTURESPROTEIN AGGREGATIONTOLCAPONETRANSTHYRETINhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain. In addition, despite current pharmacological strategies have shown to be effective against in vivo TTR aggregation by stabilizing the tetramer native structure and precluding its dissociation, they display low brain permeability. Recently, we have repurposed tolcapone as a molecule to treat systemic ATTR. Crystal structures and biophysical analysis converge to demonstrate that tolcapone binds with high affinity and specificity to three unstable leptomeningeal TTR variants, stabilizing them and, consequently, inhibiting their aggregation. Because tolcapone is an FDA-approved drug that crosses the blood-brain barrier, our results suggest that it can translate into a first disease-modifying therapy for leptomeningeal amyloidosis.Fil: Pinheiro, Francisca. Universitat Autònoma de Barcelona; EspañaFil: Varejão, Nathalia. Universitat Autònoma de Barcelona; EspañaFil: Esperante, Sebastian. Fundación para la Investigación en Infectología Infantil; Argentina. 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; ArgentinaFil: Santos, Jaime. Universitat Autònoma de Barcelona; EspañaFil: Velázquez-Campoy, Adrián. Universidad de Zaragoza; España. Aragon Institute for Health Research; España. Biomedical Research Network Center in Hepatic and Digestive Diseases; EspañaFil: Reverter, David. Universitat Autònoma de Barcelona; EspañaFil: Pallarès, Irantzu. Universitat Autònoma de Barcelona; EspañaFil: Ventura, Salvador. Universitat Autònoma de Barcelona; EspañaWiley2020-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/133306Pinheiro, Francisca; Varejão, Nathalia; Esperante, Sebastian; Santos, Jaime; Velázquez-Campoy, Adrián; et al.; Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis; Wiley; The FEBS journal; 288; 1; 5-2020; 310-3241742-464X1742-4658CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/febs.15339info:eu-repo/semantics/altIdentifier/doi/10.1111/febs.15339info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:40:40Zoai:ri.conicet.gov.ar:11336/133306instacron: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 09:40:40.471CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis
title Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis
spellingShingle Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis
Pinheiro, Francisca
AMYLOIDOSIS
CRYSTAL STRUCTURES
PROTEIN AGGREGATION
TOLCAPONE
TRANSTHYRETIN
title_short Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis
title_full Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis
title_fullStr Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis
title_full_unstemmed Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis
title_sort Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis
dc.creator.none.fl_str_mv Pinheiro, Francisca
Varejão, Nathalia
Esperante, Sebastian
Santos, Jaime
Velázquez-Campoy, Adrián
Reverter, David
Pallarès, Irantzu
Ventura, Salvador
author Pinheiro, Francisca
author_facet Pinheiro, Francisca
Varejão, Nathalia
Esperante, Sebastian
Santos, Jaime
Velázquez-Campoy, Adrián
Reverter, David
Pallarès, Irantzu
Ventura, Salvador
author_role author
author2 Varejão, Nathalia
Esperante, Sebastian
Santos, Jaime
Velázquez-Campoy, Adrián
Reverter, David
Pallarès, Irantzu
Ventura, Salvador
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AMYLOIDOSIS
CRYSTAL STRUCTURES
PROTEIN AGGREGATION
TOLCAPONE
TRANSTHYRETIN
topic AMYLOIDOSIS
CRYSTAL STRUCTURES
PROTEIN AGGREGATION
TOLCAPONE
TRANSTHYRETIN
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain. In addition, despite current pharmacological strategies have shown to be effective against in vivo TTR aggregation by stabilizing the tetramer native structure and precluding its dissociation, they display low brain permeability. Recently, we have repurposed tolcapone as a molecule to treat systemic ATTR. Crystal structures and biophysical analysis converge to demonstrate that tolcapone binds with high affinity and specificity to three unstable leptomeningeal TTR variants, stabilizing them and, consequently, inhibiting their aggregation. Because tolcapone is an FDA-approved drug that crosses the blood-brain barrier, our results suggest that it can translate into a first disease-modifying therapy for leptomeningeal amyloidosis.
Fil: Pinheiro, Francisca. Universitat Autònoma de Barcelona; España
Fil: Varejão, Nathalia. Universitat Autònoma de Barcelona; España
Fil: Esperante, Sebastian. Fundación para la Investigación en Infectología Infantil; Argentina. 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
Fil: Santos, Jaime. Universitat Autònoma de Barcelona; España
Fil: Velázquez-Campoy, Adrián. Universidad de Zaragoza; España. Aragon Institute for Health Research; España. Biomedical Research Network Center in Hepatic and Digestive Diseases; España
Fil: Reverter, David. Universitat Autònoma de Barcelona; España
Fil: Pallarès, Irantzu. Universitat Autònoma de Barcelona; España
Fil: Ventura, Salvador. Universitat Autònoma de Barcelona; España
description Hereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain. In addition, despite current pharmacological strategies have shown to be effective against in vivo TTR aggregation by stabilizing the tetramer native structure and precluding its dissociation, they display low brain permeability. Recently, we have repurposed tolcapone as a molecule to treat systemic ATTR. Crystal structures and biophysical analysis converge to demonstrate that tolcapone binds with high affinity and specificity to three unstable leptomeningeal TTR variants, stabilizing them and, consequently, inhibiting their aggregation. Because tolcapone is an FDA-approved drug that crosses the blood-brain barrier, our results suggest that it can translate into a first disease-modifying therapy for leptomeningeal amyloidosis.
publishDate 2020
dc.date.none.fl_str_mv 2020-05
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/11336/133306
Pinheiro, Francisca; Varejão, Nathalia; Esperante, Sebastian; Santos, Jaime; Velázquez-Campoy, Adrián; et al.; Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis; Wiley; The FEBS journal; 288; 1; 5-2020; 310-324
1742-464X
1742-4658
CONICET Digital
CONICET
url http://hdl.handle.net/11336/133306
identifier_str_mv Pinheiro, Francisca; Varejão, Nathalia; Esperante, Sebastian; Santos, Jaime; Velázquez-Campoy, Adrián; et al.; Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis; Wiley; The FEBS journal; 288; 1; 5-2020; 310-324
1742-464X
1742-4658
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://onlinelibrary.wiley.com/doi/abs/10.1111/febs.15339
info:eu-repo/semantics/altIdentifier/doi/10.1111/febs.15339
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 Wiley
publisher.none.fl_str_mv Wiley
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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