title: Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity.
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.
authors.affiliation: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sant'Anna
authors.affiliation: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Gallego
authors.affiliation: Molecular and Experimental Medicine Department, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Lei Z
authors.initials: LZ
authors.lastname: Robinson
authors.affiliation: 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, Porto, Portugal.
authors.forename: Alda
authors.initials: A
authors.lastname: Pereira-Henriques
authors.affiliation: 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, Porto, Portugal.
authors.forename: Nelson
authors.initials: N
authors.lastname: Ferreira
authors.affiliation: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Pinheiro
authors.affiliation: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Esperante
authors.affiliation: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
authors.forename: Irantzu
authors.initials: I
authors.lastname: Pallares
authors.affiliation: SOM-Biotech, Baldiri Reixac 4, Barcelona 08028, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Huertas
authors.affiliation: 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, Porto, Portugal.
authors.forename: Maria Rosário
authors.initials: MR
authors.lastname: Almeida
authors.affiliation: Molecular and Experimental Medicine Department, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Natàlia
authors.initials: N
authors.lastname: Reixach
authors.affiliation: SOM-Biotech, Baldiri Reixac 4, Barcelona 08028, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: Insa
authors.affiliation: Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit IQFR-CSIC-BIFI, Universidad de Zaragoza, Zaragoza 50018, Spain.|Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza 50009, Spain.|Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza 50009, Spain.|Fundación ARAID, Government of Aragón, Zaragoza 50003, Spain.
authors.forename: Adrian
authors.initials: A
authors.lastname: Velazquez-Campoy
authors.affiliation: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Reverter
authors.affiliation: SOM-Biotech, Baldiri Reixac 4, Barcelona 08028, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Reig
authors.affiliation: Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
mesh_terms: D000284:Administration, Oral; D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy*; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology / Q000627:therapeutic use*; D065098:Catechol O-Methyltransferase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D019281:Dimerization; D058492:Drug Repositioning; D064368:Healthy Volunteers; D006801:Humans; D008822:Mice, Transgenic; D008875:Middle Aged; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use*; D011228:Prealbumin / Q000187:drug effects / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy*; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D011228:Prealbumin; D000077867:Tolcapone