Potential use of glucuronylglucosyl-β-cyclodextrin as a novel therapeutic tool for familial amyloidotic polyneuropathy
Potential use of glucuronylglucosyl-β-cyclodextrin as a novel therapeutic tool for familial amyloidotic polyneuropathy
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DOI：
10.3109/13506129.2012.674988
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发表时间：
2012-06-01
影响因子：
5.5
通讯作者：
Ando, Yukio
中科院分区：
文献类型：
--
作者：
Jono, Hirofumi;Anno, Takayuki;Ando, Yukio
甲状腺素运载蛋白（transthyretin，TTR）相关的家族性淀粉样多发性神经病是由淀粉样蛋白原性甲状腺素运载蛋白（amyloidogenic transthyretin，ATTR）引起的，其特征是淀粉样纤维的全身积聚。尽管据信TTR单体形式的蛋白质错误折叠是TTR淀粉样蛋白形成的限速步骤，但没有靶向该错误折叠步骤的有效疗法可用。我们最近的研究表明，环糊精（CyDs），由葡萄糖单元组成的环状寡糖，可能与TTR相互作用，并防止蛋白质的错误折叠。在这项研究中，我们专注于并阐明6-O-α-（4-O-α-D-葡萄糖醛酸基）-D-葡萄糖基-β-CyD（GUG-beta-CyD）对TTR淀粉样蛋白形成的抑制作用。色氨酸（Trp）荧光和H-1-NMR光谱分析表明，GUG-β-CyD通过与TTR的疏水氨基酸相互作用来稳定TTR构象。此外，GUG-β-CyD在体内抑制具有人ATTR V30 M基因的转基因大鼠中的TTR沉积。总的来说，这些数据表明，GUG-β-CyD可以通过稳定其构象来抑制TTR错误折叠，从而抑制TTR淀粉样蛋白的形成。
Transthyretin (TTR)-related familial amyloidotic polyneuropathy, which is induced by amyloidogenic transthyretin (ATTR), is characterized by systemic accumulation of amyloid fibrils. Although it is believed that protein misfolding of monomeric form of TTR is a rate-limiting step for TTR amyloid formation, no effective therapy targeting this misfolding step is available. Our recent studies revealed that cyclodextrins (CyDs), cyclic oligosaccharides composed of glucose units, might interact with TTR and prevent the protein misfolding. In this study, we focused on and elucidated the inhibitory effect of 6-O-alpha-(4-O-alpha-D-Glucuronyl)-D-glucosyl-beta-CyD (GUG-beta-CyD) on TTR amyloid formation. Tryptophan (Trp) fluorescence and H-1-NMR spectroscopy analyses indicated that GUG-beta-CyD stabilized TTR conformation via interaction with the hydrophobic amino acids of TTR. Moreover, GUG-beta-CyD suppressed TTR deposition in transgenic rats possessing a human ATTR V30M gene in vivo. Collectively, these data indicate that GUG-beta-CyD may inhibit TTR misfolding by stabilizing its conformation, which, in turn, suppresses TTR amyloid formation.