Synthesis of Disulfide Surrogate Peptides Incorporating Large-Span Surrogate Bridges Through a Native-Chemical-Ligation-Assisted Diaminodiacid Strategy
Synthesis of Disulfide Surrogate Peptides Incorporating Large-Span Surrogate Bridges Through a Native-Chemical-Ligation-Assisted Diaminodiacid Strategy
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通过天然化学连接辅助二氨基二酸策略合成包含大跨度替代桥的二硫键替代肽
DOI：
10.1002/anie.201915358
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Liu Lei
中科院分区：
文献类型：
--
作者：
Qu Qian;Gao Shuai;Wu Fangming;Zhang Meng-Ge;Li Ying;Zhang Long-Hua;Bierer Donald;Tian Chang-Lin;Zheng Ji-Shen;Liu Lei
使用合成桥作为二硫键的替代物已成为解决某些含二硫键肽稳定性差的实用策略。然而，结合大跨度合成桥的肽仍然超出了现有方法的范围。在本文中，我们报告了一种天然化学连接（NCL）辅助的二氨基二酸（DADA）策略，该策略能够稳健地生成二硫键替代肽，其包含长度高达50个氨基酸的替代桥。 这种策略提供了获得一些非常理想但不可能获得的生物活性肽的二硫化物替代物的途径。通过电压钳测定、NMR和X射线晶体学验证了合成二硫键替代物的生物活性和结构;稳定性研究表明，二硫键替代物有效克服了二硫键还原和混乱问题，这些问题通常困扰着这些重要的肽。
The use of synthetic bridges as surrogates for disulfide bonds has emerged as a practical strategy to obviate the poor stability of some disulfide‐containing peptides. However, peptides incorporating large‐span synthetic bridges are still beyond the reach of existing methods. Herein, we report a native chemical ligation (NCL)‐assisted diaminodiacid (DADA) strategy that enables the robust generation of disulfide surrogate peptides incorporating surrogate bridges up to 50 amino acids in length. This strategy provides access to some highly desirable but otherwise impossible‐to‐obtain disulfide surrogates of bioactive peptide. The bioactivities and structures of the synthetic disulfide surrogates were verified by voltage clamp assays, NMR, and X‐ray crystallography; and stability studies established that the disulfide replacements effectively overcame the problems of disulfide reduction and scrambling that often plague these pharmacologically important peptides.