title: A novel bis-furan scaffold for transthyretin stabilization and amyloid inhibition.
abstract: The design and synthesis of a novel bis-furan scaffold tailored for high efficiency at inhibiting transthyretin amyloid formation is reported. In vitro results show that the discovered compounds are more efficient inhibitors of amyloid formation than tafamidis, a drug currently used in the treatment of familial amyloid polyneuropathy (FAP), despite their lower molecular weight and lipophilicity. Moreover, ex vivo experiments with the strongest inhibitor in the series, conducted in human blood plasma from normal and FAP Val30Met-transthyretin carriers, disclose remarkable affinity and selectivity profiles. The promises and challenges facing further development of this compound are discussed under the light of increasing evidence implicating transthyretin stability as a key factor not only in transthyretin amyloidoses and several associated co-morbidities, but also in Alzheimer's disease.
authors.affiliation: BSIM(2) - Drug Discovery, Parque Tecnológico de Cantanhede, 3060-197 Cantanhede, Portugal; Centro de Química de Coimbra and Departamento de Química, Universidade de Coimbra, 3004-535 Coimbra, Portugal. Electronic address: carlos.simoes@bsimsquare.com.
authors.forename: Carlos J V
authors.initials: CJV
authors.lastname: Simões
authors.affiliation: Centro de Química de Coimbra and Departamento de Química, Universidade de Coimbra, 3004-535 Coimbra, Portugal; Center for Neuroscience and Cell Biology, Universidade de Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Zaida L
authors.initials: ZL
authors.lastname: Almeida
authors.affiliation: Centro de Química de Coimbra and Departamento de Química, Universidade de Coimbra, 3004-535 Coimbra, Portugal.
authors.forename: Dora
authors.initials: D
authors.lastname: Costa
authors.affiliation: Centro de Química de Coimbra and Departamento de Química, Universidade de Coimbra, 3004-535 Coimbra, Portugal; Center for Neuroscience and Cell Biology, Universidade de Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Catarina S H
authors.initials: CSH
authors.lastname: Jesus
authors.affiliation: Centro de Química de Coimbra and Departamento de Química, Universidade de Coimbra, 3004-535 Coimbra, Portugal.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Cardoso
authors.affiliation: I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto; ICBAS - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Almeida
authors.affiliation: I3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135 Porto.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Saraiva
authors.affiliation: Centro de Química de Coimbra and Departamento de Química, Universidade de Coimbra, 3004-535 Coimbra, Portugal.
authors.forename: Teresa M V D
authors.initials: TMVD
authors.lastname: Pinho E Melo
authors.affiliation: Centro de Química de Coimbra and Departamento de Química, Universidade de Coimbra, 3004-535 Coimbra, Portugal; Center for Neuroscience and Cell Biology, Universidade de Coimbra, 3004-504 Coimbra, Portugal. Electronic address: brito@ci.uc.pt.
authors.forename: Rui M M
authors.initials: RMM
authors.lastname: Brito
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D005663:Furans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D011487:Protein Conformation; D055550:Protein Stability / Q000187:drug effects
chemical_list: D000682:Amyloid; D005663:Furans; D011228:Prealbumin; D066329:Protein Aggregates
keywords: Amyloid; Bis-furans; Lead discovery; Neurodegeneration; Transthyretin