Mu Yanshuang, Jin Shoude, Shen Jingling, Sugano Aki, Takaoka Yutaka, Qiang Lixia, Imbimbo Bruno P, Yamamura Ken-ichi, Li Zhenghua
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan; College of Life Sciences, Northeast Agriculture University, Harbin, China.
Division of Respiratory Disease, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
FEBS Lett. 2015 Mar 24;589(7):849-56. doi: 10.1016/j.febslet.2015.02.020. Epub 2015 Feb 26.
Familial amyloidotic polyneuropathy is one type of protein misfolding disease. Transthyretin (TTR) tetramer dissociation is the limiting step for amyloid fibril formation. CHF5074 (CSP-1103) stabilizes TTR tetramer in vitro by binding to the T4 binding site. Here, we used three strains of double humanized mice (mTtr(hTTRVal30/hTTRVal30), mTtr(hTTRVal30/hTTRMet30), and mTtr(hTTRMet30/hTTRMet30)) to assess whether CHF5074 stabilizes TTR tetramers in vivo. Treatment of mice with CHF5074 increased serum TTR levels by stabilizing TTR tetramers. Although the binding affinities of CHF5074 and diflunisal with TTRMet30 were similar, CHF5074 bound TTRVal30 more strongly than did diflunisal, suggesting the potent TTR-stabilizing activity of CHF5074.
家族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）四聚体解离是淀粉样纤维形成的限速步骤。CHF5074（CSP - 1103）通过与T4结合位点结合在体外稳定TTR四聚体。在此，我们使用三株双人源化小鼠（mTtr(hTTRVal30/hTTRVal30)、mTtr(hTTRVal30/hTTRMet30)和mTtr(hTTRMet30/hTTRMet30)）来评估CHF5074在体内是否能稳定TTR四聚体。用CHF5074治疗小鼠可通过稳定TTR四聚体来提高血清TTR水平。尽管CHF5074和双氯芬酸与TTRMet30的结合亲和力相似，但CHF5074与TTRVal30的结合比双氯芬酸更强，这表明CHF5074具有强大的TTR稳定活性。
