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

<div class='caption-title'>Tolcapone and tafamidis effects over WT, V122I-TTR and A25T-TTR aggregation and stability.</div>
<div class='caption-title'>Interaction of TTR with tolcapone assessed by ITC.</div>
<div class='caption-title'>Crystal structures of WT-TTR/ligand and V122I-TTR/ligand complexes.</div>
Sant'Anna R, Gallego P, Robinson LZ, Pereira-Henriques A, Ferreira N, Pinheiro F, Esperante S, Pallares I, Huertas O, Almeida MR, Reixach N, Insa R, Velazquez-Campoy A, Reverter D, Reig N, Ventura S
OpenAccess logo Nat Commun 7 10787 (2016)
Cited: 75 times
EuropePMC logo PMID: 26902880

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.

Articles - 5a6i mentioned but not cited (2)

  1. Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity. Sant'Anna R, Gallego P, Robinson LZ, Pereira-Henriques A, Ferreira N, Pinheiro F, Esperante S, Pallares I, Huertas O, Almeida MR, Reixach N, Insa R, Velazquez-Campoy A, Reverter D, Reig N, Ventura S. Nat Commun 7 10787 (2016)
  2. Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer. Zanotti G, Vallese F, Ferrari A, Menozzi I, Saldaño TE, Berto P, Fernandez-Alberti S, Berni R. PLoS One 12 e0187716 (2017)


Reviews citing this publication (34)

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