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

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Sant'Anna, R (Author) Other; Gallego, P (Author) Other; Robinson, LZ (Author) Other; Pereira Henriques, A (Author) Other; Ferreira, N (Author) Other; Pinheiro, F (Author) Other; Esperante, S (Author) Other; Pallares, I (Author) Other; Huertas, O (Author) Other; Almeida, MR (Author) ICBAS; Reixach, N (Author) Other; Insa, R (Author) Other; Velazquez Campoy, A (Author) Other; Reverter, D (Author) Other; Reig, N (Author) Other; Ventura, S (Author) Other

Journal

Title: Nature Communications

Vol. 7

ISSN: 2041-1723

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 38 Citations

Scopus - 81 Citations

Other information

Authenticus ID: P-00K-7C8

DOI: 10.1038/ncomms10787

Abstract (EN): Transthyretin (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 T-4 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13