Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.
Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.
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DOI：
10.1007/s40120-016-0040-x
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发表时间：
2016-06
影响因子：
3.7
通讯作者：
Huertas P
中科院分区：
文献类型：
--
作者：
Coelho T;Merlini G;Bulawa CE;Fleming JA;Judge DP;Kelly JW;Maurer MS;Planté-Bordeneuve V;Labaudinière R;Mundayat R;Riley S;Lombardo I;Huertas P
甲状腺素运载蛋白（TTR）转运视黄醇结合蛋白-维生素A复合物，是血液中甲状腺素的次要转运蛋白。其四聚体结构经历限速解离和单体错误折叠，使得TTR聚集或变成淀粉样蛋白。TTR基因的突变通常使四聚体不稳定和/或加速四聚体解离，促进淀粉样蛋白生成。TTR相关的淀粉样变性是一种罕见的、致命的、蛋白质错误折叠的疾病，其特征在于形成可变结构的可溶性聚集体和淀粉样蛋白的组织沉积。TTR淀粉样变性表现为一系列表现，包括进行性神经病和/或心肌病。直到最近，唯一被接受的阻止遗传性TTR淀粉样变性进展的治疗方法是肝移植，其用淀粉样蛋白生成较少的野生型TTR替代突变型TTR的肝来源。Tafamidis葡甲胺是一种合理设计的非NSAID苯并恶唑衍生物，以高亲和力和选择性与TTR结合，并在动力学上稳定四聚体，减缓单体形成、错误折叠和淀粉样蛋白生成。Tafamidis是第一个被批准用于减缓TTR家族性淀粉样多发性神经病周围神经功能损害进展的药物治疗。在这里，我们描述了tafamlutamine的作用机制，并回顾了临床数据，证明tafamlutamine治疗减缓了早期Val 30 Met淀粉样变性患者的神经功能恶化，保持了营养状态以及生活质量。本文的在线版本（doi：10.1007/s40120-016-0040-x）包含补充材料，可供授权用户使用。
Transthyretin (TTR) transports the retinol-binding protein–vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are rare, fatal, protein-misfolding disorders, characterized by formation of soluble aggregates of variable structure and tissue deposition of amyloid. The TTR amyloidoses present with a spectrum of manifestations, encompassing progressive neuropathy and/or cardiomyopathy. Until recently, the only accepted treatment to halt progression of hereditary TTR amyloidosis was liver transplantation, which replaces the hepatic source of mutant TTR with the less amyloidogenic wild-type TTR. Tafamidis meglumine is a rationally designed, non-NSAID benzoxazole derivative that binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis. Tafamidis is the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in TTR familial amyloid polyneuropathy. Here we describe the mechanism of action of tafamidis and review the clinical data, demonstrating that tafamidis treatment slows neurologic deterioration and preserves nutritional status, as well as quality of life in patients with early-stage Val30Met amyloidosis. The online version of this article (doi:10.1007/s40120-016-0040-x) contains supplementary material, which is available to authorized users.