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

Ricardo Sant'Anna, Pablo Gallego, Lei Z. Robinson, Alda Pereira-Henriques, Nelson Ferreira, Francisca Pinheiro, Sebastian Esperante, Irantzu Pallares, Oscar Huertas, Maria Rosário Almeida, Natàlia Reixach, Raul Insa, Adrian Velazquez-Campoy, David Reverter, Núria Reig () and Salvador Ventura ()
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Ricardo Sant'Anna: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona
Pablo Gallego: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona
Lei Z. Robinson: The Scripps Research Institute
Alda Pereira-Henriques: Molecular Neurobiology, IBMC- Instituto de Biologia Molecular e Celular i3S - Instituto de Investigação e Inovação em Saúde and ICBAS- Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto
Nelson Ferreira: Molecular Neurobiology, IBMC- Instituto de Biologia Molecular e Celular i3S - Instituto de Investigação e Inovação em Saúde and ICBAS- Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto
Francisca Pinheiro: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona
Sebastian Esperante: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona
Irantzu Pallares: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona
Oscar Huertas: SOM-Biotech
Maria Rosário Almeida: Molecular Neurobiology, IBMC- Instituto de Biologia Molecular e Celular i3S - Instituto de Investigação e Inovação em Saúde and ICBAS- Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto
Natàlia Reixach: The Scripps Research Institute
Raul Insa: SOM-Biotech
Adrian Velazquez-Campoy: Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit IQFR-CSIC-BIFI, Universidad de Zaragoza
David Reverter: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona
Núria Reig: SOM-Biotech
Salvador Ventura: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10787

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