Table_1_Bicyclic Pyrrolidine-Isoxazoline γ Amino Acid: A Constrained Scaffold for Stabilizing α-Turn Conformation in Isolated Peptides.DOCX

Unnatural amino acids have tremendously expanded the folding possibilities of peptides and peptide mimics. While α,α-disubstituted and β-amino acids are widely studied, γ-derivatives have been less exploited. Here we report the conformational study on the bicyclic unnatural γ amino acid, 4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]isoxazole-3-carboxylic acid 1. In model peptides, the (+)-(3aR6aS)-enantiomer is able to stabilize α-turn conformation when associated to glycine, as showed by 1H-NMR, FT-IR, and circular dichroism experiments, and molecular modeling studies. α-turn is a structural motif occurring in many biologically active protein sites, although its stabilization on isolated peptides is quite uncommon. Our results make the unnatural γ-amino acid 1 of particular interest for the development of bioactive peptidomimetics.

非天然氨基酸（unnatural amino acids）极大地拓展了肽与肽模拟物的折叠潜能。尽管α,α-二取代氨基酸与β-氨基酸的研究已较为广泛，但γ-取代氨基酸衍生物的相关探索仍相对不足。本文针对双环非天然γ-氨基酸（bicyclic unnatural γ amino acid）4,5,6,6a-四氢-3aH-吡咯并[3,4-d]异噁唑-3-羧酸1开展构象研究。在模型肽体系中，(+)-(3aR,6aS)-对映异构体与甘氨酸结合时，能够稳定α-转角（α-turn）构象，该结论通过氢核磁共振波谱（1H-NMR）、傅里叶变换红外光谱（FT-IR）、圆二色谱（circular dichroism）实验及分子模拟研究得到证实。α-转角是众多生物活性蛋白位点中存在的结构基序，但其在孤立肽中的稳定作用却较为罕见。本研究结果使得该非天然γ-氨基酸1在开发生物活性肽模拟物领域具备了特殊的应用价值。