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| Home > Articles > Published articles > Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity |
(Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí") (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí") (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular) (Instituto de Ciências Biomédicas de Abel Salazar (Porto, Portugal)) (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular) (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
| Date: | 2016 |
| 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 T 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. |
| Grants: | Ministerio de Economía y Competitividad BFU2013-47064-P Ministerio de Economía y Competitividad BFU2013-44763 Ministerio de Economía y Competitividad BFU2012-37116 Ministerio de Ciencia e Innovación BFU2010-19451 |
| Note: | Altres ajuts: S.V. has been granted an ICREA ACADEMIA award. SOM Biotech was funded by the Spanish Ministry of Health DIN 10-13 grant and the Catalan Competitiveness Agency FINEBT10-2-0037 grant. N. Reig and R.I. were funded by a Torres Quevedo grant by the Spanish Ministry of Economy and Competitiveness. |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Administration, Oral ; Amyloid neuropathies, Familial ; Animals ; Benzophenones ; Catechol O-methyltransferase inhibitors ; Cell line ; Dimerization ; Drug repositioning ; Healthy volunteers ; Humans ; Mice, Transgenic ; Middle aged ; Nitrophenols ; Prealbumin ; Protein aggregation, Pathological |
| Published in: | Nature communications, Vol. 7 (2016) , art. 10787, ISSN 2041-1723 |
| Related work: | Sant'Anna, Ricardo; Gallego Alonso, Pablo; Robinson, Lei Z.; [et al.]. «Author Correction : Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity ». Nature communications, Vol. 14 (February 2023) https://doi.org/10.1038/s41467-023-36239-z |
