Repositioning Tolcapone as a potent inhibitor of transthyretin amyloidogenesis and its associated cellular toxicity
Salvador Ventura¹
1Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193-Bellaterra, Spain.
Background:
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 the TTR amyloidoses.
Material and Methods:
Here, we used biophysical, cell biology and in vivo studies to repurpose Tolcapone, an FDA-approved molecule for Parkinson’s disease, as a very potent TTR aggregation inhibitor.
Results and Discussion:
Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. The crystal structures of Tolcapone bound to wild type TTR and to the V122I cardiomyopathy-associated variant explain why this molecule is a better amyloid inhibitor than Tafamidis, so far the only drug in the market to treat the TTR amyloidoses.
Conclusions:
Overall, Tolcapone, already in clinical trials, is a strong candidate for therapeutic intervention in these diseases, including those ocurring in the central nervous system, for which no small molecule approach exist.
Salvador Ventura¹
1Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193-Bellaterra, Spain.
Background:
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 the TTR amyloidoses.
Material and Methods:
Here, we used biophysical, cell biology and in vivo studies to repurpose Tolcapone, an FDA-approved molecule for Parkinson’s disease, as a very potent TTR aggregation inhibitor.
Results and Discussion:
Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. The crystal structures of Tolcapone bound to wild type TTR and to the V122I cardiomyopathy-associated variant explain why this molecule is a better amyloid inhibitor than Tafamidis, so far the only drug in the market to treat the TTR amyloidoses.
Conclusions:
Overall, Tolcapone, already in clinical trials, is a strong candidate for therapeutic intervention in these diseases, including those ocurring in the central nervous system, for which no small molecule approach exist.
