Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade
Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade
复制标题
DOI：
10.1073/pnas.1121005109
复制
发表时间：
2012-06-12
影响因子：
11.1
通讯作者：
Labaudiniere, Richard
中科院分区：
文献类型：
--
作者：
Bulawa, Christine E.;Connelly, Stephen;Labaudiniere, Richard
甲状腺素运载蛋白淀粉样变性（ATTR）是一种以进行性神经病变和/或心肌病为特征的致死性疾病。ATTR是由甲状腺素运载蛋白（TTR）的聚集引起的，TTR是一种天然的四聚体蛋白，参与甲状腺素和维生素A-视黄醇结合蛋白复合物的转运。导致常染色体显性形式疾病的TTR内的突变促进四聚体解离、单体错误折叠和聚集，尽管野生型TTR也可在老年患者中形成淀粉样蛋白原纤维。由于四聚体解离是TTR淀粉样蛋白生成中的限速步骤，靶向治疗集中在动力学稳定四聚体的小分子上，抑制TTR淀粉样蛋白原纤维形成。一种这样的化合物，他法莫司葡胺（Fx-1006 A），最近完成了用于治疗甲状腺素运载蛋白型家族性淀粉样多发性神经病（TTR-FAP）的II/III期试验，并证明了V30 M TTR突变杂合子患者的疾病进展减缓。在这里，我们描述了分子和结构的基础上TTR四聚体的稳定，由tafamaltine。Tafamidis选择性结合四聚体的两个正常未占据的甲状腺素结合位点，并具有负协同性（K（d）类似于2 nM和200 nM），并在动力学上稳定TTR。患者来源的TTR的淀粉样蛋白生成变体，包括动力学和代谢不太稳定的突变体，也通过tafamlutamine结合而稳定。他夫明结合TTR的晶体结构表明，结合稳定了较弱的二聚体-二聚体界面，防止解离，这是淀粉样蛋白生成的限速步骤。
The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A-retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K(d)s similar to 2 nM and similar to 200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.