Discovery of γ-Mangostin as an Amyloidogenesis Inhibitor.
Discovery of γ-Mangostin as an Amyloidogenesis Inhibitor.
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DOI：
10.1038/srep13570
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发表时间：
2015-08-27
影响因子：
4.6
通讯作者：
Mizuguchi M
中科院分区：
文献类型：
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作者：
Yokoyama T;Ueda M;Ando Y;Mizuguchi M
甲状腺素运载蛋白 (TTR) 是一种参与人类遗传性淀粉样变性的同源四聚体蛋白。发现和开发抑制TTR淀粉样原纤维形成的小分子是这些疾病的治疗策略之一。在此，我们发现 γ-mangostin (γ-M) 是 V30M 淀粉样变 TTR 淀粉样原纤维形成的有效抑制剂。体外结合测定表明，γ-M 是所选呫吨酮衍生物中最有效的，它与甲状腺素 (T4) 结合位点结合并稳定了 TTR 四聚体。 X射线晶体分析揭示了γ-M的对角结合模式和T4结合位点上氯离子的两个结合位点。 α-山竹素复合物中的一个氯离子被水分子取代，α-山竹素复合物是 γ-M 的甲基化衍生物。 γ-M 更强的抑制能力可以通过与氯离子的额外氢键来解释。本研究将 γ-M 确立为 TTR 纤维化的新型抑制剂。
Transthyretin (TTR) is a homotetrameric protein involved in human hereditary amyloidoses. The discovery and development of small molecules that inhibit the amyloid fibril formation of TTR is one of the therapeutic strategies for these diseases. Herein, we discovered that γ-mangostin (γ-M) is an effective inhibitor against the amyloid fibril formation of V30M amyloidogenic TTR. In-vitro binding assays revealed that γ-M was the most potent of the selected xanthone derivatives, and it bound to the thyroxine (T4)-binding sites and stabilized the TTR tetramer. X-ray crystallographic analysis revealed the diagonal binding mode of γ-M and the two binding sites of chloride ions at the T4-binding site. One of the chloride ions was replaced with a water molecule in the α-mangostin complex, which is a methylated derivative of γ-M. The stronger inhibitory potency of γ-M could be explained by the additional hydrogen bonds with the chloride ion. The present study establishes γ-M as a novel inhibitor of TTR fibrillization.