Division of Chemistry and Structural Biology, ARC Centre of Excellence for Innovations in Peptide & Protein Science, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Angew Chem Int Ed Engl. 2022 Jul 18;61(29):e202203995. doi: 10.1002/anie.202203995. Epub 2022 May 25.
Aromatic groups are key mediators of protein-membrane association at cell surfaces, contributing to hydrophobic effects and π-membrane interactions. Here we show electrostatic and hydrophobic influences of aromatic ring substituents on membrane affinity and cell uptake of helical, cyclic and cell penetrating peptides. Hydrophobicity is important, but subtle changes in electrostatic surface potential, dipoles and polarizability also enhance association with phospholipid membranes and cell uptake. A combination of fluorine and sulfur substituents on an aromatic ring induces microdipoles that enhance cell uptake of 12-residue peptide inhibitors of p53-HDM2 interaction and of cell-penetrating cyclic peptides. These aromatic motifs can be readily inserted into peptide sidechains to enhance their cell uptake.
芳香族基团是细胞表面蛋白质-膜相互作用的关键介质，有助于疏水性效应和π-膜相互作用。在这里，我们展示了芳香环取代基对螺旋、环状和细胞穿透肽的膜亲和力和细胞摄取的静电和疏水性影响。疏水性很重要，但静电表面电位、偶极子和极化率的细微变化也会增强与磷脂膜的结合和细胞摄取。在芳香环上引入氟和硫取代基会产生微偶极子，从而增强对 p53-HDM2 相互作用的 12 残基肽抑制剂和细胞穿透环肽的细胞摄取。这些芳香族基序可以很容易地插入到肽侧链中，以增强它们的细胞摄取。
