Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, USA.
Org Biomol Chem. 2018 Nov 28;16(46):8933-8939. doi: 10.1039/c8ob02535e.
Hydrocarbon stapling and PEGylation are distinct strategies for enhancing the conformational stability and/or pharmacokinetic properties of peptide and protein drugs. Here we combine these approaches by incorporating asparagine-linked O-allyl PEG oligomers at two positions within the β-sheet protein WW, followed by stapling of the PEGs via olefin metathesis. The impact of stapling two sites that are close in primary sequence is small relative to the impact of PEGylation alone and depends strongly on PEG length. In contrast, stapling of two PEGs that are far apart in primary sequence but close in tertiary structure provides substantially more stabilization, derived mostly from an entropic effect. Comparison of PEGylation + stapling vs. alkylation + stapling at the same positions in WW reveals that both approaches provide similar overall levels of conformational stability.
烃 stapling 和 PEGylation 是增强肽和蛋白质药物构象稳定性和/或药代动力学特性的两种截然不同的策略。在这里，我们通过在 β-折叠蛋白 WW 的两个位置结合连接有烯丙基的 O-聚乙二醇寡聚物，将这两种方法结合起来，然后通过烯烃复分解使 PEG 键合。与单独 PEGylation 相比，在一级序列上靠近的两个位置 stapling 的影响相对较小，并且强烈依赖于 PEG 长度。相比之下，在三级结构上接近但在一级序列上相距较远的两个 PEG 的 stapling 提供了更多的稳定性，主要源于熵效应。在 WW 的相同位置比较 PEGylation + stapling 与 alkylation + stapling 表明，这两种方法提供了相似的构象稳定性。
