000106145 001__ 106145
000106145 005__ 20220426091139.0
000106145 0247_ $$2doi$$a10.1111/febs.15339
000106145 0248_ $$2sideral$$a118295
000106145 037__ $$aART-2020-118295
000106145 041__ $$aeng
000106145 100__ $$aPinheiro, F.
000106145 245__ $$aTolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis
000106145 260__ $$c2020
000106145 5060_ $$aAccess copy available to the general public$$fUnrestricted
000106145 5203_ $$aHereditary transthyretin amyloidosis (ATTR) is a disease characterized by the extracellular deposition of transthyretin (TTR) amyloid fibrils. Highly destabilizing TTR mutations cause leptomeningeal amyloidosis, a rare, but fatal, disorder in which TTR aggregates in the brain. The disease remains intractable, since liver transplantation, the reference therapy for systemic ATTR, does not stop mutant TTR production in the brain. In addition, despite current pharmacological strategies have shown to be effective against in vivo TTR aggregation by stabilizing the tetramer native structure and precluding its dissociation, they display low brain permeability. Recently, we have repurposed tolcapone as a molecule to treat systemic ATTR. Crystal structures and biophysical analysis converge to demonstrate that tolcapone binds with high affinity and specificity to three unstable leptomeningeal TTR variants, stabilizing them and, consequently, inhibiting their aggregation. Because tolcapone is an FDA-approved drug that crosses the blood-brain barrier, our results suggest that it can translate into a first disease-modifying therapy for leptomeningeal amyloidosis. Databases PDB codes for A25T-TTR, V30G-TTR, and Y114C-TTR bound to tolcapone are 6TXV, 6TXW, and 6XTK, respectively.
000106145 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/BIO2016-783-78310-R
000106145 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000106145 590__ $$a5.542$$b2020
000106145 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b72 / 297 = 0.242$$c2020$$dQ1$$eT1
000106145 592__ $$a1.981$$b2020
000106145 593__ $$aBiochemistry$$c2020$$dQ1
000106145 593__ $$aMolecular Biology$$c2020$$dQ1
000106145 593__ $$aCell Biology$$c2020$$dQ1
000106145 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000106145 700__ $$aVarejao, N.
000106145 700__ $$aEsperante, S.
000106145 700__ $$aSantos, J.
000106145 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy, A.$$uUniversidad de Zaragoza
000106145 700__ $$aReverter, D.
000106145 700__ $$aPallares, I.
000106145 700__ $$aVentura, S.
000106145 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000106145 773__ $$g288, 1 (2020), 310-324$$pFEBS J.$$tFEBS Journal$$x1742-464X
000106145 8564_ $$s753167$$uhttps://zaguan.unizar.es/record/106145/files/texto_completo.pdf$$yPostprint
000106145 8564_ $$s1699366$$uhttps://zaguan.unizar.es/record/106145/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint
000106145 909CO $$ooai:zaguan.unizar.es:106145$$particulos$$pdriver
000106145 951__ $$a2022-04-26-08:55:55
000106145 980__ $$aARTICLE