Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
Main Author: | |
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Publication Date: | 2016 |
Other Authors: | , , , , , , , , , , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Download full: | http://hdl.handle.net/10216/108240 |
Summary: | 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. |
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Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicityFamilial amyloid polyneuropathyIsothermal titration calorimetrySenile systemic amyloidosisProtein misfolding diseasesNative-stateIn-vitroPhysiological conditionsKinetic stabilizationTetramer dissociationFibril formationTransthyretin (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.Nature Publishing Group20162016-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfapplication/pdfhttp://hdl.handle.net/10216/108240eng2041-172310.1038/ncomms10787Sant'Anna, RGallego, PRobinson, LPereira-Henriques, AFerreira, NPinheiro, FEsperante, SPallares, IHuertas, OAlmeida, MReixach, NInsa, RVelazquez-Campoy, AReverter, DReig, NVentura, Sinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-29T16:10:15Zoai:repositorio-aberto.up.pt:10216/108240Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:38:28.811786Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
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, R Familial amyloid polyneuropathy Isothermal titration calorimetry Senile systemic amyloidosis Protein misfolding diseases Native-state In-vitro Physiological conditions Kinetic stabilization Tetramer dissociation Fibril formation |
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 |
author |
Sant'Anna, R |
author_facet |
Sant'Anna, R Gallego, P Robinson, L Pereira-Henriques, A Ferreira, N Pinheiro, F Esperante, S Pallares, I Huertas, O Almeida, M Reixach, N Insa, R Velazquez-Campoy, A Reverter, D Reig, N Ventura, S |
author_role |
author |
author2 |
Gallego, P Robinson, L Pereira-Henriques, A Ferreira, N Pinheiro, F Esperante, S Pallares, I Huertas, O Almeida, M Reixach, N Insa, R Velazquez-Campoy, A Reverter, D Reig, N Ventura, S |
author2_role |
author author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Sant'Anna, R Gallego, P Robinson, L Pereira-Henriques, A Ferreira, N Pinheiro, F Esperante, S Pallares, I Huertas, O Almeida, M Reixach, N Insa, R Velazquez-Campoy, A Reverter, D Reig, N Ventura, S |
dc.subject.por.fl_str_mv |
Familial amyloid polyneuropathy Isothermal titration calorimetry Senile systemic amyloidosis Protein misfolding diseases Native-state In-vitro Physiological conditions Kinetic stabilization Tetramer dissociation Fibril formation |
topic |
Familial amyloid polyneuropathy Isothermal titration calorimetry Senile systemic amyloidosis Protein misfolding diseases Native-state In-vitro Physiological conditions Kinetic stabilization Tetramer dissociation Fibril formation |
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 2016-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10216/108240 |
url |
http://hdl.handle.net/10216/108240 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2041-1723 10.1038/ncomms10787 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
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:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799136292164861952 |