Makura Yui, Ueda Atsushi, Kato Takuma, Iyoshi Akihiro, Higuchi Mei, Doi Mitsunobu, Tanaka Masakazu
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka 569-1094, Japan.
Int J Mol Sci. 2021 May 19;22(10):5364. doi: 10.3390/ijms22105364.
Hydrocarbon stapling is a useful tool for stabilizing the secondary structure of peptides. Among several methods, hydrocarbon stapling at , + 1 positions was not extensively studied, and their secondary structures are not clarified. In this study, we investigate , + 1 hydrocarbon stapling between -4-allyloxy-l-proline and various olefin-tethered amino acids. Depending on the ring size of the stapled side chains and structure of the olefin-tethered amino acids, or -selectivities were observed during the ring-closing metathesis reaction (/ was up to 8.5:1 for 17-14-membered rings and up to 1:20 for 13-membered rings). We performed X-ray crystallographic analysis of hydrocarbon stapled peptide at , + 1 positions. The X-ray crystallographic structure suggested that the , + 1 staple stabilizes the peptide secondary structure to the right-handed α-helix. These findings are especially important for short oligopeptides because the employed stapling method uses two minimal amino acid residues adjacent to each other.
烃基环化修饰是稳定肽二级结构的一种有用工具。在几种方法中，在i,i + 1位置的烃基环化修饰尚未得到广泛研究，其二级结构也未阐明。在本研究中，我们研究了-4-烯丙氧基-L-脯氨酸与各种烯烃连接的氨基酸之间的i,i + 1烃基环化修饰。根据环化侧链的环大小和烯烃连接的氨基酸的结构，在关环复分解反应中观察到了Z或E选择性（对于17 - 14元环，Z/E高达8.5:1，对于13元环高达1:20）。我们对i,i + 1位置的烃基环化修饰肽进行了X射线晶体学分析。X射线晶体学结构表明，i,i + 1环化修饰将肽二级结构稳定为右手α-螺旋。这些发现对于短寡肽尤为重要，因为所采用的环化修饰方法使用了彼此相邻的两个最小氨基酸残基。
