Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity.

SANTANNA R; GALLEGO P; ROBINSON LZ; ALDA PEREIRA-HENRIQUES; NELSON FERREIA; FRANCISCA PINHEIRO; SEBASTIAN ESPERANTE; NURIA REIG; SALVADOR VENTURA

NATURE COMMUNICATIONS

Nature Publishing Group

Año: 2016

2041-1723

Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemicamyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native statestabilizers 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 inmice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound towild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks betterinto the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTRamyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloidpolyneuropathy, is a strong candidate for therapeutic intervention in these diseases, includingthose affecting the central nervous system, for which no small-molecule therapy exists.