000048371 001__ 48371
000048371 005__ 20231116120807.0
000048371 0247_ $$2doi$$a10.1038/ncomms10787
000048371 0248_ $$2sideral$$a94101
000048371 037__ $$aART-2016-94101
000048371 041__ $$aeng
000048371 100__ $$aSant'Anna, R.
000048371 245__ $$aRepositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
000048371 260__ $$c2016
000048371 5060_ $$aAccess copy available to the general public$$fUnrestricted
000048371 5203_ $$aTransthyretin (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.
000048371 536__ $$9info:eu-repo/grantAgreement/EUR/SUDOE/INTERREG/NEUROMED-SOE4-P1-E831$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P$$9info:eu-repo/grantAgreement/ES/MICINN/BFU2010-19451
000048371 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000048371 590__ $$a12.124$$b2016
000048371 591__ $$aMULTIDISCIPLINARY SCIENCES$$b3 / 63 = 0.048$$c2016$$dQ1$$eT1
000048371 592__ $$a6.413$$b2016
000048371 593__ $$aBiochemistry, Genetics and Molecular Biology (miscellaneous)$$c2016$$dQ1
000048371 593__ $$aPhysics and Astronomy (miscellaneous)$$c2016$$dQ1
000048371 593__ $$aChemistry (miscellaneous)$$c2016$$dQ1
000048371 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000048371 700__ $$aGallego, P.
000048371 700__ $$aRobinson, L.Z.
000048371 700__ $$aPereira-Henriques, A.
000048371 700__ $$aFerreira, N.
000048371 700__ $$aPinheiro, F.
000048371 700__ $$aEsperante, S.
000048371 700__ $$aPallares, I.
000048371 700__ $$aHuertas, O.
000048371 700__ $$aAlmeida, M.R.
000048371 700__ $$aReixach, N.
000048371 700__ $$aInsa, R.
000048371 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy, A.$$uUniversidad de Zaragoza
000048371 700__ $$aReverter, D.
000048371 700__ $$aReig, N.
000048371 700__ $$aVentura, S.
000048371 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000048371 773__ $$g7 (2016), 10787 [13 pp]$$tNature communications$$x2041-1723
000048371 8564_ $$s1097270$$uhttps://zaguan.unizar.es/record/48371/files/texto_completo.pdf$$yVersión publicada
000048371 8564_ $$s73350$$uhttps://zaguan.unizar.es/record/48371/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000048371 909CO $$ooai:zaguan.unizar.es:48371$$particulos$$pdriver
000048371 951__ $$a2023-11-16-11:59:50
000048371 980__ $$aARTICLE