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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\u2019s disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer <jats:italic>in vivo<\/jats:italic> 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 T<jats:sub>4<\/jats:sub> 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.<\/jats:p>","DOI":"10.1038\/ncomms10787","type":"journal-article","created":{"date-parts":[[2016,2,23]],"date-time":"2016-02-23T10:06:25Z","timestamp":1456221985000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":162,"title":["Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity"],"prefix":"10.1038","volume":"7","author":[{"given":"Ricardo","family":"Sant'Anna","sequence":"first","affiliation":[]},{"given":"Pablo","family":"Gallego","sequence":"additional","affiliation":[]},{"given":"Lei Z.","family":"Robinson","sequence":"additional","affiliation":[]},{"given":"Alda","family":"Pereira-Henriques","sequence":"additional","affiliation":[]},{"given":"Nelson","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Francisca","family":"Pinheiro","sequence":"additional","affiliation":[]},{"given":"Sebastian","family":"Esperante","sequence":"additional","affiliation":[]},{"given":"Irantzu","family":"Pallares","sequence":"additional","affiliation":[]},{"given":"Oscar","family":"Huertas","sequence":"additional","affiliation":[]},{"given":"Maria","family":"Ros\u00e1rio Almeida","sequence":"additional","affiliation":[]},{"given":"Nat\u00e0lia","family":"Reixach","sequence":"additional","affiliation":[]},{"given":"Raul","family":"Insa","sequence":"additional","affiliation":[]},{"given":"Adrian","family":"Velazquez-Campoy","sequence":"additional","affiliation":[]},{"given":"David","family":"Reverter","sequence":"additional","affiliation":[]},{"given":"N\u00faria","family":"Reig","sequence":"additional","affiliation":[]},{"given":"Salvador","family":"Ventura","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2016,2,23]]},"reference":[{"key":"BFncomms10787_CR1","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","volume":"75","author":"F Chiti","year":"2006","unstructured":"Chiti, F. & Dobson, C. 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