Diaminodiacid Bridges to Improve Folding and Tune the Bioactivity of Disulfide-Rich Peptides
Diaminodiacid Bridges to Improve Folding and Tune the Bioactivity of Disulfide-Rich Peptides
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DOI：
10.1002/anie.201500699
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发表时间：
2015-11-23
影响因子：
16.6
通讯作者：
Tian, Chang-Lin
中科院分区：
文献类型：
--
作者：
Guo, Ye;Sun, De-Meng;Tian, Chang-Lin
含有三个或更多个二硫键的富含二硫键的肽是有前途的治疗和诊断剂，但它们的制备通常受到繁琐且低产率的折叠过程的限制。我们发现，一个单一的胱氨酸到二氨基二酸的替代可以显着增加富含二硫键的肽的折叠效率，从而提高其生产产量。该策略的实用性通过合成和折叠芋螺毒素SIIIA、临床前激素铁调素和胰蛋白酶抑制剂EETI-II的衍生物来证明。NMR和X射线晶体学研究证实，这些富含二硫键的肽衍生物保留了正确的三维构象。此外，胱氨酸到二氨基二酸的置换使得能够进行结构调整，从而产生比天然肽具有更高生物活性的EETI-II衍生物。
Disulfide-rich peptides containing three or more disulfide bonds are promising therapeutic and diagnostic agents, but their preparation is often limited by the tedious and low-yielding folding process. We found that a single cystine-to-diaminodiacid replacement could significantly increase the folding efficiency of disulfide-rich peptides and thus improve their production yields. The practicality of this strategy was demonstrated by the synthesis and folding of derivatives of the mu-conotoxin SIIIA, the preclinical hormone hepcidin, and the trypsin inhibitor EETI-II. NMR and X-ray crystallography studies confirmed that these derivatives of disulfide-rich peptide retained the correct three-dimensional conformations. Moreover, the cystine-to-diaminodiacid replacement enabled structural tuning, thereby leading to an EETI-II derivative with higher bioactivity than the native peptide.