Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Bioorg Chem. 2024 Apr;145:107220. doi: 10.1016/j.bioorg.2024.107220. Epub 2024 Feb 17.
In this study, we explored the potential of the photoremovable o-nitrobenzyl (oNB) group as a tool to manipulate the membrane permeability and regulate the conformation of linear peptides by means of experimental and computational studies. We found that the introduction of one or more oNB groups markedly increased the permeability and altered the conformation, as compared to the corresponding unmodified peptides. We thoroughly investigated the impact of peptide length, number of oNB group, oNB insertion position, and introduction of N- and C-terminal protecting groups on the passive membrane permeability by means of parallel artificial membrane permeability assay (PAMPA). Photoreaction of peptides containing one or two oNB groups proceeded cleanly in moderate to high yields, releasing the unprotected parent linear peptide. The oNB-modified peptides showed a cis/trans conformational equilibrium, while after photolysis, the unprotected linear peptides showed only the trans-amide conformation. Furthermore, a comprehensive comparison of oNB-modified peptides and N-methylated peptides was conducted, encompassing conformational analysis and physicochemical properties. N-Substituted peptides favored a folded-like structure, which may contribute to the improvement in permeability.
在这项研究中，我们通过实验和计算研究探索了光解 o-硝基苄基（oNB）基团作为一种工具来调节线性肽的膜通透性和构象的潜力。与相应的未修饰肽相比，我们发现引入一个或多个 oNB 基团会显著增加通透性并改变构象。我们通过平行人工膜透过性测定（PAMPA）彻底研究了肽的长度、oNB 基团的数量、oNB 插入位置以及 N-和 C-末端保护基团的引入对被动膜通透性的影响。含有一个或两个 oNB 基团的肽的光反应以中等至高产率顺利进行，释放出未保护的原始线性肽。oNB 修饰的肽显示顺/反构象平衡，而光解后，未保护的线性肽仅显示反酰胺构象。此外，还对 oNB 修饰肽和 N-甲基化肽进行了全面比较，包括构象分析和物理化学性质。N-取代肽有利于折叠样结构，这可能有助于提高通透性。
