Structural Biology

Biography

Salvador Ventura is Full Professor and Head of the Protein Folding and Conformational Diseases Laboratory at Universitat Autònoma de Barcelona. Work at his lab focuses on protein folding, misfolding and amyloid formation, with special emphasis on their impact on protein homeostasis and conformational disorders. He has contributed with more than 170 research articles to these topics. He has been a Postdoctoral Fellow at EMBL-Heidelberg and visiting scientist at Harvard Medical School (US) and Karolinska Institutet (Sweden). 

Abstract

Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal amyloidosis. TTR tetramer dissociation precedes pathological TTR aggregation. Despite TTR stabilizers being promising drugs to treat TTR amyloidoses, none of them is approved by the Food and Drug Administration (FDA). Repositioning existing drugs for new indications is becoming increasingly important in drug development. Here, we repurposed tolcapone, an FDA-approved molecule for Parkinson’s disease, as a very potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the tetramer in vivo and inhibits TTR cytotoxicity. In contrast to most TTR stabilizers, it exhibits high affinity for both TTR thyroxine-binding sites. The crystal structure of tolcapone-bound TTR explains why this molecule is a better amyloid inhibitor than tafamidis, so far the only drug in the market to treat the TTR amyloidoses. Overall, tolcapone, already in clinical trials, is a strong candidate for therapeutic intervention in these diseases.