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

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 in...

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Autores: Garcia de Carvalho Pinheiro, Francisca|||0000-0003-3778-1528, Varejão, Nathalia|||0000-0002-6952-8896, Esperante, Sebastián|||0000-0002-5778-6871, Santos Suárez, Jaime|||0000-0001-9045-7765, Velázquez-Campoy, Adrián|||0000-0001-5702-4538, Reverter Cendrós, David|||0000-0002-5347-0992, Pallarès i Goitiz, Irantzu|||0000-0002-8205-2060, Ventura, Salvador|||0000-0002-9652-6351
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:323744
Acceso en línea:https://ddd.uab.cat/record/323744
https://dx.doi.org/urn:doi:10.1111/febs.15339
Access Level:acceso abierto
Palabra clave:Amyloidosis
Crystal structures
Protein aggregation
Tolcapone
Transthyretin
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spelling Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosisGarcia de Carvalho Pinheiro, Francisca|||0000-0003-3778-1528Varejão, Nathalia|||0000-0002-6952-8896Esperante, Sebastián|||0000-0002-5778-6871Santos Suárez, Jaime|||0000-0001-9045-7765Velázquez-Campoy, Adrián|||0000-0001-5702-4538Reverter Cendrós, David|||0000-0002-5347-0992Pallarès i Goitiz, Irantzu|||0000-0002-8205-2060Ventura, Salvador|||0000-0002-9652-6351AmyloidosisCrystal structuresProtein aggregationTolcaponeTransthyretinHereditary 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. 22021-01-0120212021-01-01Articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/323744https://dx.doi.org/urn:doi:10.1111/febs.15339reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 BIO2016-78310-Ropen accesshttp://purl.org/coar/access_right/c_abf2Aquest material està protegit per drets d'autor i/o drets afins. Podeu utilitzar aquest material en funció del que permet la legislació de drets d'autor i drets afins d'aplicació al vostre cas. Per a d'altres usos heu d'obtenir permís del(s) titular(s) de drets.https://rightsstatements.org/vocab/InC/1.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:3237442026-06-06T12:50:31Z
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
Garcia de Carvalho Pinheiro, Francisca|||0000-0003-3778-1528
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 Garcia de Carvalho Pinheiro, Francisca|||0000-0003-3778-1528
Varejão, Nathalia|||0000-0002-6952-8896
Esperante, Sebastián|||0000-0002-5778-6871
Santos Suárez, Jaime|||0000-0001-9045-7765
Velázquez-Campoy, Adrián|||0000-0001-5702-4538
Reverter Cendrós, David|||0000-0002-5347-0992
Pallarès i Goitiz, Irantzu|||0000-0002-8205-2060
Ventura, Salvador|||0000-0002-9652-6351
author Garcia de Carvalho Pinheiro, Francisca|||0000-0003-3778-1528
author_facet Garcia de Carvalho Pinheiro, Francisca|||0000-0003-3778-1528
Varejão, Nathalia|||0000-0002-6952-8896
Esperante, Sebastián|||0000-0002-5778-6871
Santos Suárez, Jaime|||0000-0001-9045-7765
Velázquez-Campoy, Adrián|||0000-0001-5702-4538
Reverter Cendrós, David|||0000-0002-5347-0992
Pallarès i Goitiz, Irantzu|||0000-0002-8205-2060
Ventura, Salvador|||0000-0002-9652-6351
author_role author
author2 Varejão, Nathalia|||0000-0002-6952-8896
Esperante, Sebastián|||0000-0002-5778-6871
Santos Suárez, Jaime|||0000-0001-9045-7765
Velázquez-Campoy, Adrián|||0000-0001-5702-4538
Reverter Cendrós, David|||0000-0002-5347-0992
Pallarès i Goitiz, Irantzu|||0000-0002-8205-2060
Ventura, Salvador|||0000-0002-9652-6351
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
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 2021
dc.date.none.fl_str_mv 2
2021-01-01
2021
2021-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/323744
https://dx.doi.org/urn:doi:10.1111/febs.15339
url https://ddd.uab.cat/record/323744
https://dx.doi.org/urn:doi:10.1111/febs.15339
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 BIO2016-78310-R
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://rightsstatements.org/vocab/InC/1.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://rightsstatements.org/vocab/InC/1.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
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