Repositioning of the Anthelmintic Drugs Bithionol and Triclabendazole as Transthyretin Amyloidogenesis Inhibitors
Repositioning of the Anthelmintic Drugs Bithionol and Triclabendazole as Transthyretin Amyloidogenesis Inhibitors
复制标题
驱虫药 Bithionol 和 Triclabendmaze 作为运甲状腺素蛋白淀粉样蛋白生成抑制剂的重新定位
DOI：
10.1021/acs.jmedchem.1c00823
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发表时间：
2021
影响因子：
7.3
通讯作者：
Mizuguchi Mineyuki
中科院分区：
文献类型：
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作者：
Yokoyama Takeshi;Kashihara Mirai;Mizuguchi Mineyuki
甲状腺素运载蛋白（TTR）是TTR淀粉样变性（ATTR淀粉样变性）的致病蛋白，ATTR淀粉样变性是以TTR淀粉样纤维在特定器官中沉积为特征的疾病的总称。ATTR淀粉样变性可以通过小分子的结合稳定TTR四聚体来改善。在这里，我们发现临床驱虫药bithionol（42）和triclabendazole（43）有效地抑制淀粉样蛋白生成变体V30 M-TTR的聚集。使用荧光探针的竞争结合试验显示，42与V30 M-TTR的结合亲和力显著高于一类药物tafamlutamine（1），43的结合亲和力与1相似。晶体学和热力学分析表明，42有效地占据了TTR的卤素结合槽，产生了有利的结合熵。体外驱虫药物的多方面研究有可能将这些药物重新定位为ATTR淀粉样变性抑制剂。
Transthyretin (TTR) is a causative protein of TTR amyloidosis (ATTR amyloidosis), a general term for diseases characterized by deposition of TTR amyloid fibrils in specific organs. ATTR amyloidosis can be ameliorated by stabilization of the TTR tetramer through the binding of small molecules. Here, we show that the clinical anthelmintic drugs bithionol (42) and triclabendazole (43) potently inhibit aggregation of the amyloidogenic variant V30M-TTR. A competitive binding assay using a fluorescence probe showed that the binding affinity of42with V30M-TTR was significantly higher than that of the first-in-class drug tafamidis (1), and the binding affinity of43was similar to that of1. The crystallographic and thermodynamic analysis revealed that42efficiently occupied the halogen-binding grooves of TTR, resulting in the favorable binding entropy. Multifacetedin vitrostudies of anthelmintic drugs have the potential to reposition these drugs as ATTR amyloidosis inhibitors.