Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity.
Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity.
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DOI：
10.1038/ncomms10787
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发表时间：
2016-02-23
影响因子：
16.6
通讯作者：
Ventura S
中科院分区：
文献类型：
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作者：
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
转甲状腺素(TTR)是一种血浆同四聚体蛋白，与致命性系统性淀粉样变性有关。TTR四聚体解离先于病理性TTR四聚体。天然状态稳定剂是治疗TTR淀粉样变性的有前途的药物。在这里，我们改变了Tolcapone的用途，它是FDA批准的一种治疗帕金森病的分子，作为一种有效的TTR聚集抑制因子。Tolcapone与人血浆中的TTR特异结合，在小鼠和人类体内稳定天然四聚体，并抑制TTR的细胞毒作用。与野生型TTR和V122I心肌病相关变体结合的Tolcapone的晶体结构表明，它与TTRT4口袋的对接比他法米迪更好，他法米迪是目前市场上唯一治疗TTR淀粉样变性的药物。这些数据表明，已经在进行家族性淀粉样多发性神经病临床试验的托卡彭是治疗这些疾病的有力候选者，包括那些影响中枢神经系统的疾病，这些疾病尚不存在小分子疗法。转甲状腺素的错误折叠可导致淀粉样蛋白聚集障碍，可以通过用他法米迪稳定四聚体形式来治疗。在这里，作者证明了已经被FDA批准用于帕金森病的药物Tolcapone具有强大的转甲状腺素稳定功能，并且由于它可以穿过血脑屏障，可能是治疗中枢神经系统淀粉样变性的一种更好的选择。
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. Misfolding of transthyretin can cause amyloid aggregation disorders that can be treated by stabilizing the tetrameric form with tafamidis. Here the authors show that tolcapone, a drug already FDA-approved for Parkinson disease, has strong transthyretin stabilizing function and might be a superior therapeutic option for CNS amyloidosis as it can cross the blood brain barrier.