Abstract：
Cyclisation of peptides by forming thioether (lanthionine), disulfide (cystine) or methylene thioacetal bridges between side chains is established as an important tool to stabilise a given structure, enhance metabolic stability and optimise both potency and selectivity. However, a systematic comparative study of the effects of differing bridging modalities on peptide conformation has not previously been carried out. In this paper, we have used the NMR deconvolution algorithm, NAMFIS, to determine the conformational ensembles, in aqueous solution, of three cyclic analogues of angiotensin(1-7), incorporating either disulfide, or non-reduceable thioether or methylene thioacetal bridges. We demonstrate that the major solution conformations are conserved between the different bridged peptides, but the distribution of conformations differs appreciably. This suggests that subtle differences in ring size and bridging structure can be exploited to fine-tune the conformational properties of cyclic peptides, which may modulate their bioactivities.
摘要：
通过形成硫醚（羊毛硫氨酸）使肽环化，侧链之间的二硫化物（胱氨酸）或亚甲基硫代缩醛桥被确立为稳定给定结构的重要工具，增强代谢稳定性并优化效力和选择性。然而,以前尚未对不同桥接方式对肽构象的影响进行系统的比较研究。在本文中,我们使用了核磁共振去卷积算法，NAMFIS,为了确定构象集合，在水溶液中，血管紧张素的三种环状类似物（1-7），掺入二硫化物，或不可还原的硫醚或亚甲基硫代缩醛桥。我们证明了主要的溶液构象在不同的桥接肽之间是保守的，但是构象的分布明显不同。这表明可以利用环大小和桥接结构的细微差异来微调环肽的构象特性，这可能会调节它们的生物活性。
