Repurposing benzbromarone for familial amyloid polyneuropathy: a new transthyretin tetramer stabilizer

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 effecti...

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Authors: Cotrina, Ellen, Oliveira, Ângela, Leite, José Pedro, Llop, Jordi, Gales, Luis, Quintana, Jordi, Cardoso, Isabel, Arsequell, Gemma
Format: article
Status:Published version
Publication Date:2020
Country:España
Institution:Universitat Pompeu Fabra
Repository:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/48276
Online Access:http://hdl.handle.net/10230/48276
http://dx.doi.org/10.3390/ijms21197166
Access Level:Open access
Keyword:Benzbromarone
Dibromophenol scaffold
Drug
Drug repurposing
Native kinetic stabilization
Transthyretin
Transthyretin tetramer stabilizer
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spelling Repurposing benzbromarone for familial amyloid polyneuropathy: a new transthyretin tetramer stabilizerCotrina, EllenOliveira, ÂngelaLeite, José PedroLlop, JordiGales, LuisQuintana, JordiCardoso, IsabelArsequell, GemmaBenzbromaroneDibromophenol 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.I.C. works under the Investigator FCT Program which is financed by national funds through FCT and co-financed by ESF through HPOP, type 4.2, Promotion of Scientific Employment. I.C. acknowledges a grant from Fundação Millennium bcp. G.A. acknowledges a grant from Fundació Marató de TV3, Spain (project ref. 20140330-31-32-33-34) and from Spanish MINECO (grant CTQ2016-76840-R).MDPI202120212020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/48276http://dx.doi.org/10.3390/ijms21197166reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésinfo:eu-repo/grantAgreement/ES/1PE/CTQ2016-76840-RCopyright © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/482762026-06-12T07:21:37Z
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, Ellen
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
dc.creator.none.fl_str_mv Cotrina, Ellen
Oliveira, Ângela
Leite, José Pedro
Llop, Jordi
Gales, Luis
Quintana, Jordi
Cardoso, Isabel
Arsequell, Gemma
author Cotrina, Ellen
author_facet Cotrina, Ellen
Oliveira, Ângela
Leite, José Pedro
Llop, Jordi
Gales, Luis
Quintana, Jordi
Cardoso, Isabel
Arsequell, Gemma
author_role author
author2 Oliveira, Ângela
Leite, José Pedro
Llop, Jordi
Gales, Luis
Quintana, Jordi
Cardoso, Isabel
Arsequell, Gemma
author2_role author
author
author
author
author
author
author
dc.subject.none.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
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/48276
http://dx.doi.org/10.3390/ijms21197166
url http://hdl.handle.net/10230/48276
http://dx.doi.org/10.3390/ijms21197166
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/ES/1PE/CTQ2016-76840-R
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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