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

• Published in: Nature communications Vol. 7; no. 1; p. 10787
• Main Authors: Sant'Anna, Ricardo, Gallego, Pablo, Robinson, Lei Z., Pereira-Henriques, Alda, Ferreira, Nelson, Pinheiro, Francisca, Esperante, Sebastian, Pallares, Irantzu, Huertas, Oscar, Rosário Almeida, Maria, Reixach, Natàlia, Insa, Raul, Velazquez-Campoy, Adrian, Reverter, David, Reig, Núria, Ventura, Salvador
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.02.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/309/436; 631/443/319/1642; 692/308; 82; 82/80; Administration, Oral; Agglomeration; Amyloid; Amyloid Neuropathies, Familial - drug therapy; Amyloidogenesis; Amyloidosis; Animals; Benzophenones - pharmacology; Benzophenones - therapeutic use; Biocompatibility; Blood plasma; Blood-brain barrier; Cardiomyopathy; Catechol O-Methyltransferase Inhibitors - pharmacology; Catechol O-Methyltransferase Inhibitors - therapeutic use; Cell Line; Central nervous system; Clinical trials; Cytotoxicity; Dimerization; Docks; Drug Repositioning; Healthy Volunteers; Humanities and Social Sciences; Humans; Mice, Transgenic; Middle Aged; Movement disorders; multidisciplinary; Neurodegenerative diseases; Neurotoxicity; Nitrophenols - pharmacology; Nitrophenols - therapeutic use; Parkinson's disease; Polyneuropathy; Prealbumin - drug effects; Prealbumin - metabolism; Protein Aggregation, Pathological - drug therapy; Science; Tolcapone; Toxicity; Transthyretin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10787

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. Misfolding of transthyretin can cause amyloid aggregation disorders that can be treated by stabilizing the tetrameric form with tafamidis. Here the authors show that tolcapone, a drug already FDA-approved for Parkinson disease, has strong transthyretin stabilizing function and might be a superior therapeutic option for CNS amyloidosis as it can cross the blood brain barrier.