Sant'Anna Ricardo, Gallego Pablo, Robinson Lei Z, Pereira-Henriques Alda, Ferreira Nelson, Pinheiro Francisca, Esperante Sebastian, Pallares Irantzu, Huertas Oscar, Almeida Maria Rosário, Reixach Natàlia, Insa Raul, Velazquez-Campoy Adrian, Reverter David, Reig Núria, Ventura Salvador
Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
Molecular and Experimental Medicine Department, The Scripps Research Institute, La Jolla, California 92037, USA.
Nat Commun. 2016 Feb 23;7:10787. doi: 10.1038/ncomms10787.
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.
转甲状腺素蛋白（TTR）是一种血浆同四聚体蛋白，与致命的全身性淀粉样变性有关。TTR四聚体解离先于病理性TTR聚集。天然状态稳定剂是治疗TTR淀粉样变性的有前景的药物。在此，我们将已获美国食品药品监督管理局（FDA）批准用于治疗帕金森病的托卡朋重新用作一种有效的TTR聚集抑制剂。托卡朋在人血浆中特异性结合TTR，在小鼠和人体内稳定天然四聚体，并抑制TTR细胞毒性。托卡朋与野生型TTR以及与V122I心肌病相关变体结合的晶体结构表明，它比目前市场上唯一用于治疗TTR淀粉样变性的药物塔非酰胺更能很好地嵌入TTR的T4口袋。这些数据表明，已在进行家族性淀粉样多神经病临床试验的托卡朋是对这些疾病进行治疗干预的有力候选药物，包括那些影响中枢神经系统且尚无小分子疗法的疾病。
