Repurposing benzbromarone for familial amyloid polyneuropathy: a new transthyretin tetramer stabilizer
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- dc.contributor.author Cotrina, Ellen
- dc.contributor.author Oliveira, Ângela
- dc.contributor.author Leite, José Pedro
- dc.contributor.author Llop, Jordi
- dc.contributor.author Gales, Luis
- dc.contributor.author Quintana, Jordi
- dc.contributor.author Cardoso, Isabel
- dc.contributor.author Arsequell, Gemma
- dc.date.accessioned 2021-07-22T07:11:52Z
- dc.date.available 2021-07-22T07:11:52Z
- dc.date.issued 2020
- dc.description.abstract 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.
- dc.description.sponsorship 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).
- dc.format.mimetype application/pdf
- dc.identifier.citation Cotrina EY, Oliveira Â, Leite JP, Llop J, Gales L, Quintana J, et al. Repurposing benzbromarone for familial amyloid polyneuropathy: a new transthyretin tetramer stabilizer. Int J Mol Sci. 2020 Sep 28; 21(19): 7166. DOI: 10.3390/ijms21197166
- dc.identifier.doi http://dx.doi.org/10.3390/ijms21197166
- dc.identifier.issn 1422-0067
- dc.identifier.uri http://hdl.handle.net/10230/48276
- dc.language.iso eng
- dc.publisher MDPI
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/CTQ2016-76840-R
- dc.rights Copyright © 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/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword Benzbromarone
- dc.subject.keyword Dibromophenol scaffold
- dc.subject.keyword Drug
- dc.subject.keyword Drug repurposing
- dc.subject.keyword Native kinetic stabilization
- dc.subject.keyword Transthyretin
- dc.subject.keyword Transthyretin tetramer stabilizer
- dc.title Repurposing benzbromarone for familial amyloid polyneuropathy: a new transthyretin tetramer stabilizer
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion