{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T05:23:23Z","timestamp":1770960203446,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T00:00:00Z","timestamp":1601251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008666","name":"FUNDACI\u00d3 LA MARAT\u00d3 DE TV3","doi-asserted-by":"publisher","award":["20140330-31-32-33-34"],"award-info":[{"award-number":["20140330-31-32-33-34"]}],"id":[{"id":"10.13039\/100008666","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms21197166","type":"journal-article","created":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T20:03:02Z","timestamp":1601323382000},"page":"7166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer"],"prefix":"10.3390","volume":"21","author":[{"given":"Ellen Y.","family":"Cotrina","sequence":"first","affiliation":[{"name":"Institut de Qu\u00edmica Avan\u00e7ada de Catalunya (I.Q.A.C.-C.S.I.C.), 08034 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7940-4141","authenticated-orcid":false,"given":"\u00c2ngela","family":"Oliveira","sequence":"additional","affiliation":[{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"}]},{"given":"Jos\u00e9 Pedro","family":"Leite","sequence":"additional","affiliation":[{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), 4050-013 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0821-9838","authenticated-orcid":false,"given":"Jordi","family":"Llop","sequence":"additional","affiliation":[{"name":"CIC biomaGUNE, Basque Research and Technology Alliance (BRTA), 20014 San Sebastian, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8352-6539","authenticated-orcid":false,"given":"Luis","family":"Gales","sequence":"additional","affiliation":[{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), 4050-013 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7059-7418","authenticated-orcid":false,"given":"Jordi","family":"Quintana","sequence":"additional","affiliation":[{"name":"Research Programme on Biomedical Informatics, Universitat Pompeu Fabra (UPF-IMIM), 08003 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-7055","authenticated-orcid":false,"given":"Isabel","family":"Cardoso","sequence":"additional","affiliation":[{"name":"IBMC\u2014Instituto de Biologia Molecular e Celular, 4200-135 Porto, Portugal"},{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), 4050-013 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-3738","authenticated-orcid":false,"given":"Gemma","family":"Arsequell","sequence":"additional","affiliation":[{"name":"Institut de Qu\u00edmica Avan\u00e7ada de Catalunya (I.Q.A.C.-C.S.I.C.), 08034 Barcelona, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/0022-2836(78)90368-6","article-title":"Structure of prealbumin: Secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 \u00c5","volume":"121","author":"Blake","year":"1978","journal-title":"J. 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