Qiang Lixia, Guan Yanxia, Li Xiangshun, Liu Li, Mu Yanshuang, Sugano Aki, Takaoka Yutaka, Sakaeda Toshiyuki, Imbimbo Bruno P, Yamamura Ken-Ichi, Jin Shoude, Li Zhenghua
a Division of Respiratory Disease , The Fourth Affiliated Hospital of Harbin Medical University , Harbin , China.
b Yamamura Project Laboratory, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto , Kumamoto , Japan.
Amyloid. 2017 Mar;24(1):42-51. doi: 10.1080/13506129.2017.1308348. Epub 2017 Apr 10.
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.
遗传性淀粉样多神经病是一种蛋白质错误折叠疾病。转甲状腺素蛋白（TTR）是一种同四聚体血清蛋白，TTR四聚体解离是淀粉样纤维形成的限速步骤。因此，预防TTR解离是一种有前景的治疗方法，一些TTR稳定剂已被批准用于治疗TTR淀粉样变性。CSP-1103（CHF5074）是一种缺乏环氧化酶抑制活性的非甾体抗炎衍生物。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。我们之前已经表明，在人源化小鼠的Ttr位点和Rbp4位点，口服CSP-1103通过稳定TTR四聚体来提高血清TTR水平。为了确定CSP-1103是否能在人体内稳定TTR四聚体，在一项双盲、安慰剂对照、平行组研究中，对48名健康人类志愿者口服多次CSP-1103，持续两周。在正常或变性应激条件下，CSP-1103治疗以剂量依赖的方式稳定TTR四聚体，从而提高血清TTR水平。在体外，血清与CSP-1103或双氟尼酸预孵育可提高TTR四聚体的稳定性。计算机模拟分析显示，CSP-1103在pH 7.0时与TTR的结合亲和力与他氟米特相似，从而证实CSP-1103具有强大的TTR稳定活性。
