Total Synthesis of Human Hepcidin through Regioselective Disulfide-Bond Formation by using the Safety-Catch Cysteine Protecting Group 4,4′-Dimethylsulfinylbenzhydryl
Total Synthesis of Human Hepcidin through Regioselective Disulfide-Bond Formation by using the Safety-Catch Cysteine Protecting Group 4,4′-Dimethylsulfinylbenzhydryl
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DOI：
10.1002/anie.201310103
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发表时间：
2014-03-10
影响因子：
16.6
通讯作者：
Alewood, Paul F.
中科院分区：
文献类型：
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作者：
Dekan, Zoltan;Mobli, Mehdi;Alewood, Paul F.
设计和开发了安全捕获半胱氨酸保护基团 S-4,4'-二甲基亚磺酰二苯甲基 (Msbh)，以扩展在富含半胱氨酸的肽中区域选择性形成二硫键的合成策略的能力。对含有四个二硫键的人铁调素进行了定向区域选择性合成，并在比以前更符合生理学的条件下获得了高分辨率的 NMR 结构。相反，用先前指定的邻位二硫键连接合成的铁调素在相似条件下表现出显着的构象异质性。人铁调素的两种合成形式诱导铁转运蛋白内化，表观 EC50 值为 2.0（天然倍数，1）和 4.4 nm（非天然倍数，2），其中 2 在铁转运蛋白表达细胞存在下异构化为 1。
A safety-catch cysteine protecting group, S-4,4'-dimethylsulfinylbenzhydryl (Msbh), was designed and developed to expand the capabilities of synthetic strategies for the regioselective formation of disulfide bonds in cysteine-rich peptides. The directed regioselective synthesis of human hepcidin, which contains four disulfide bonds, was undertaken and led to a high-resolution NMR structure under more physiologically relevant conditions than previously. Conversely, hepcidin synthesized with the formerly assigned vicinal disulfide-bond connectivity displayed significant conformational heterogeneity under similar conditions. The two synthetic forms of human hepcidin induced ferroportin internalization with apparent EC50 values of 2.0 (native fold, 1) and 4.4 nm (non-native fold, 2), with 2 undergoing isomerization to 1 in the presence of ferroportin expressing cells.