Orthogonal Cysteine-Penicillamine Disulfide Pairing for Directing the Oxidative Folding of Peptides.
Orthogonal Cysteine-Penicillamine Disulfide Pairing for Directing the Oxidative Folding of Peptides.
复制标题
DOI：
10.1021/jacs.5b10779
复制
发表时间：
2015-11
影响因子：
15
通讯作者：
Yiwu Zheng;Linxiang Zhai;Yibing Zhao;Chuanliu Wu
中科院分区：
文献类型：
--
作者：
Yiwu Zheng;Linxiang Zhai;Yibing Zhao;Chuanliu Wu
合成肽的精确二硫配对通常采用正交保护基团策略或依赖于一级序列操作。正交二硫键对技术在指导多环肽从完全还原肽中合理折叠方面具有广阔的应用前景。在这里，我们报道了半胱氨酸（Cys）和青霉胺（Pen）之间的正交性以及Cys-Cys/Pen-Pen二硫化物的形成。通过在空气中直接氧化或在氧化还原介质中硫醇-二硫交换，可以利用正交Cys-Pen二硫化物对高选择性地生产某些（多）环结构（甚至是没有异构体的单一结构）。这一策略使得不需要保护基团的多环肽的合理折叠、序列操纵和复杂的合成反应成为现实，从而为肽群落提供了宝贵的资产，并将极大地促进多环肽治疗和配体的发展。
Precise disulfide pairing in synthetic peptides usually is achieved using orthogonal protecting group strategies or relies on primary sequence manipulation. Orthogonal disulfide pairing technology should be promising for directing the rational folding of multicyclic peptides from the fully reduced peptides. Here, we report a discovery on the orthogonality between heterodisulfide pairing of cysteine (Cys) and penicillamine (Pen) and formation of Cys-Cys/Pen-Pen homodisulfides. The orthogonal Cys-Pen disulfide pairing can be exploited for highly selective production of certain (multi)cyclic structures (or even a sole structure without isomers) through direct oxidation in air or thiol-disulfide exchanges in redox media. This strategy makes rational folding of multicyclic peptides without protecting groups, sequence manipulation, and complex synthetic reactions a reality, thus providing invaluable assets to peptide communities, and should greatly benefit the development of multicyclic peptide therapeutics and ligands.