CSP-1103 (CHF5074) stabilizes human transthyretin in healthy human subjects
CSP-1103 (CHF5074) stabilizes human transthyretin in healthy human subjects
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CSP-1103 (CHF5074) 可稳定健康人类受试者中的人转甲状腺素蛋白
DOI：
10.1080/13506129.2017.1308348
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发表时间：
2017-01-01
影响因子：
5.5
通讯作者：
Li, Zhenghua
中科院分区：
文献类型：
--
作者：
Qiang, Lixia;Guan, Yanxia;Li, Zhenghua
遗传性淀粉样多神经病是一种蛋白质错误折叠疾病。转甲状腺素（TTR）是一种同四聚体血清蛋白，TTR四聚体解离是淀粉样蛋白纤维形成的限制步骤。因此，预防TTR解离是一种很有前景的治疗方法，一些TTR稳定剂已被批准用于治疗TTR淀粉样变性。CSP-1103 （CHF5074）是一种非甾体抗炎衍生物，缺乏环氧化酶抑制活性。在体外，CSP-1103通过与甲状腺素（T4）结合位点结合来稳定TTR四聚体。我们之前的研究表明，通过稳定人源化小鼠TTR位点和Rbp4位点的TTR四聚体，口服CSP-1103可提高血清TTR水平。为了确定CSP-1103是否能稳定人体内的TTR四聚体，在一项双盲、安慰剂对照、平行组研究中，对48名健康的人类志愿者口服多剂量CSP-1103，持续两周。CSP-1103治疗在正常或变性应激条件下以剂量依赖的方式稳定TTR四聚体，从而增加血清TTR水平。血清与CSP-1103或地氟尼柳体外预孵育可提高TTR四聚体的稳定性。计算机模拟分析表明，CSP-1103在pH 7.0时与TTR的结合亲和力与tafamidis相似，从而证实了CSP-1103具有强大的TTR稳定活性。
Hereditary amyloid polyneuropathy is a type of protein misfolding disease. Transthyretin (TTR) is a homotetrameric serum protein and TTR tetramer dissociation is the limiting step in amyloid fibril formation. Thus, prevention of TTR dissociation is a promising therapeutic approach and some TTR stabilizers have been approved for the treatment of TTR amyloidosis. CSP-1103 (CHF5074) is a non-steroidal anti-inflammatory derivative that lacks cyclooxygenase inhibitory activity. In vitro, CSP-1103 stabilizes the TTR tetramer by binding to the thyroxine (T4) binding site. We have previously shown that serum TTR levels were increased by oral CSP-1103 administration through stabilization of TTR tetramers in humanized mice at both the Ttr locus and the Rbp4 locus. To determine whether CSP-1103 stabilizes TTR tetramers in humans, multiple CSP-1103 oral doses were administered for two weeks to 48 healthy human volunteers in a double-blind, placebo-controlled, parallel-group study. CSP-1103 treatment stabilized TTR tetramers in a dose-dependent manner under normal or denaturing stress conditions, thereby increasing serum TTR levels. Preincubation of serum with CSP-1103 or diflunisal in vitro increased the TTR tetramer stability. Computer simulation analysis revealed that the binding affinities of CSP-1103 with TTR at pH 7.0 were similar to those of tafamidis, thus confirming that CSP-1103 has potent TTR-stabilizing activity.