Authors: Sant’Anna, Ricardo; Gallego, Pablo; Robinson, Lei Z.; Pereira Henriques, Alda; Ferreira, Nelson; Pinheiro, Francisca; Esperante, Sebastian; Pallares, Irantzu; Huertas, Oscar; Almeida, Maria Rosario; Reixach, Natalia; Insa, Raul; Velazquez Campoy, Adrian; Reverter, David; Reig, Nuria; Ventura, Salvador
Publication Date: 2016.
Language: English.
Abstract:
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 T4 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.
Author affiliation: Sant’Anna, Ricardo. Universitat Autonoma de Barcelona; España
Author affiliation: Gallego, Pablo. Universitat Autonoma de Barcelona; España
Author affiliation: Robinson, Lei Z.. The Scripps Research Institute; Estados Unidos
Author affiliation: Pereira Henriques, Alda. Universidad de Porto; Portugal
Author affiliation: Ferreira, Nelson. Universidad de Porto; Portugal
Author affiliation: Pinheiro, Francisca. Universitat Autonoma de Barcelona; España
Author affiliation: Esperante, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad de Barcelona; España
Author affiliation: Pallares, Irantzu. Universitat Autonoma de Barcelona; España
Author affiliation: Huertas, Oscar. SOM-Biotech; España
Author affiliation: Almeida, Maria Rosario. Universidad de Porto; Portugal
Author affiliation: Reixach, Natalia. The Scripps Research Institute; Estados Unidos
Author affiliation: Insa, Raul. SOM-Biotech; España
Author affiliation: Velazquez Campoy, Adrian. Fundación ARAID; España. Universidad de Zaragoza; España. Instituto de Investigación Sanitaria de Aragón; España
Author affiliation: Reverter, David. Universitat Autonoma de Barcelona; España
Author affiliation: Reig, Nuria. SOM-Biotech; España
Author affiliation: Ventura, Salvador. Universitat Autonoma de Barcelona; España
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas