Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizer
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/10216/143501 |
Resumo: | Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC50 similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers. |
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Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizerBenzbromaroneDibromophenol scaffoldDrugDrug repurposingNative kinetic stabilizationTransthyretinTransthyretin tetramer stabilizerTransthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC50 similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers.MDPI20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10216/143501eng1661-659610.3390/ijms21197166Cotrina, EYOliveira, ÂLeite, JPLlop, JGales, LQuintana, JCardoso, IArsequell, Ginfo: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:RCAAP2023-11-29T12:46:40Zoai:repositorio-aberto.up.pt:10216/143501Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T23:26:31.153143Repositório 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 |
Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizer |
title |
Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizer |
spellingShingle |
Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizer Cotrina, EY Benzbromarone Dibromophenol scaffold Drug Drug repurposing Native kinetic stabilization Transthyretin Transthyretin tetramer stabilizer |
title_short |
Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizer |
title_full |
Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizer |
title_fullStr |
Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizer |
title_full_unstemmed |
Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizer |
title_sort |
Repurposing benzbromarone for familial amyloid polyneuropathy: A new transthyretin tetramer stabilizer |
author |
Cotrina, EY |
author_facet |
Cotrina, EY Oliveira, Â Leite, JP Llop, J Gales, L Quintana, J Cardoso, I Arsequell, G |
author_role |
author |
author2 |
Oliveira, Â Leite, JP Llop, J Gales, L Quintana, J Cardoso, I Arsequell, G |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Cotrina, EY Oliveira, Â Leite, JP Llop, J Gales, L Quintana, J Cardoso, I Arsequell, G |
dc.subject.por.fl_str_mv |
Benzbromarone Dibromophenol scaffold Drug Drug repurposing Native kinetic stabilization Transthyretin Transthyretin tetramer stabilizer |
topic |
Benzbromarone Dibromophenol scaffold Drug Drug repurposing Native kinetic stabilization Transthyretin Transthyretin tetramer stabilizer |
description |
Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC50 similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020 2020-01-01T00:00:00Z |
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 |
https://hdl.handle.net/10216/143501 |
url |
https://hdl.handle.net/10216/143501 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1661-6596 10.3390/ijms21197166 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
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 |
instacron_str |
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 |
repository.mail.fl_str_mv |
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1799135571658932225 |