Inhibiting transthyretin amyloid fibril formation via protein stabilization
Inhibiting transthyretin amyloid fibril formation via protein stabilization
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DOI：
10.1073/pnas.93.26.15051
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发表时间：
1996-12-24
影响因子：
11.1
通讯作者：
Kelly, JW
中科院分区：
文献类型：
--
作者：
Miroy, GJ;Lai, ZH;Kelly, JW
甲状腺素运载蛋白（TTR）淀粉样纤维的形成在家族性淀粉样多发性神经病和老年性系统性淀粉样变性中被全身观察到，并且似乎是这些疾病的致病因子。（10.8 μ M）在体外有效地抑制TTR原纤维形成，并且通过稳定四聚体防止解离和随后的淀粉样原纤维形成所需的构象变化来实现，此外，与TTR结合的非天然配体2，4，6-三碘苯酚以略微增加的亲和力也通过这种机制抑制TTR原纤维的形成。（与构象变化相关）形成单体淀粉样蛋白生成中间体，其在不存在甲状腺素的情况下自组装成淀粉样蛋白，但在存在甲状腺素的情况下不自组装成淀粉样蛋白，这些结果证明了使用小分子稳定潜在的淀粉样蛋白原人类蛋白质的天然折叠的可行性，从而防止构象变化，这似乎是几种人类淀粉样蛋白疾病中的共同联系。这种策略和由进一步开发产生的化合物应该证明可用于严格评估淀粉样蛋白假说，即，TTR淀粉样蛋白沉积与家族性淀粉样多发性神经病和老年系统性淀粉样变性发病之间的因果关系
Transthyretin (TTR) amyloid fibril formation is observed systemically in familial amyloid polyneuropathy and senile systemic amyloidosis and appears to be the causative agent in these diseases, Herein, we demonstrate conclusively that thyroxine (10.8 mu M) inhibits TTR fibril formation efficiently in vitro and does so by stabilizing the tetramer against dissociation and the subsequent conformational changes required for amyloid fibril formation, In addition, the nonnative ligand 2,4,6-triiodophenol, which binds to TTR with slightly increased affinity also inhibits TTR fibril formation by this mechanism, Sedimentation velocity experiments were employed to show that TTR undergoes dissociation (linked to a conformational change) to form the monomeric amyloidogenic intermediate, which self-assembles into amyloid in the absence, but not in the presence of thyroxine, These results demonstrate the feasibility of using small molecules to stabilize the native fold of a potentially amyloidogenic human protein, thus preventing the conformational changes, which appear to be the common link in several human amyloid diseases, This strategy and the compounds resulting from further development should prove useful for critically evaluating the amyloid hypothesis-i.e., the putative cause-and-effect relationship between TTR amyloid deposition and the onset of familial amyloid polyneuropathy and senile systemic amyloidosis.