Foldamer-mediated manipulation of a pre-amyloid toxin.
Foldamer-mediated manipulation of a pre-amyloid toxin.
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DOI：
10.1038/ncomms11412
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发表时间：
2016-04-25
影响因子：
16.6
通讯作者：
Miranker AD
中科院分区：
文献类型：
--
作者：
Kumar S;Birol M;Schlamadinger DE;Wojcik SP;Rhoades E;Miranker AD
无序的蛋白质，如那些阿尔茨海默氏症和帕金森氏症的核心蛋白质，对于结构靶向的治疗设计来说特别难处理。在这里，我们展示了合成的折叠剂捕获疾病相关多肽结构的能力。低聚喹啉酰胺有一个明确的折叠，其核心不含溶剂，独立于其向外投射的可衍生部分。胰岛淀粉样多肽(IAPP)是2型糖尿病β细胞病理的核心多肽。提出了一种四喹啉，它可以稳定IAPP的淀粉样蛋白前α螺旋构象。这种带电的双阴离子化合物很容易溶于水缓冲溶液，但在没有细胞帮助的情况下就能穿过生物膜：这种出人意料的能力是其可逆折叠能力的结果。四喹啉与细胞内的IAPP特异性对接，使β-细胞免于毒性。综上所述，我们的工作支持这样一种观点，即稳定塑料蛋白质的无毒构象是一种可行的策略，可以使用低聚喹啉酰胺来解决细胞毒拯救问题。形成淀粉样纤维的内在无序蛋白质很难用传统的治疗方法来靶向。在这里，作者报告了一种低聚喹啉衍生物，它结合了人类胰岛淀粉样多肽，稳定了降低其细胞毒性的α-螺旋结构。
Disordered proteins, such as those central to Alzheimer's and Parkinson's, are particularly intractable for structure-targeted therapeutic design. Here we demonstrate the capacity of a synthetic foldamer to capture structure in a disease relevant peptide. Oligoquinoline amides have a defined fold with a solvent-excluded core that is independent of its outwardly projected, derivatizable moieties. Islet amyloid polypeptide (IAPP) is a peptide central to β-cell pathology in type II diabetes. A tetraquinoline is presented that stabilizes a pre-amyloid, α-helical conformation of IAPP. This charged, dianionic compound is readily soluble in aqueous buffer, yet crosses biological membranes without cellular assistance: an unexpected capability that is a consequence of its ability to reversibly fold. The tetraquinoline docks specifically with intracellular IAPP and rescues β-cells from toxicity. Taken together, our work here supports the thesis that stabilizing non-toxic conformers of a plastic protein is a viable strategy for cytotoxic rescue addressable using oligoquinoline amides. Intrinsically disordered proteins that form amyloid fibrils are hard to target with traditional therapeutic approaches. Here, the authors report on an oligoquinoline derivative that binds the human islet amyloid polypeptide, stabilising an alpha-helical structure that reduces its cellular toxicity.