Department of Biointerface Chemistry, Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan.
J Med Chem. 2023 May 25;66(10):7054-7062. doi: 10.1021/acs.jmedchem.3c00628. Epub 2023 May 15.
The development of cyclic peptides that exhibit pH-sensitive membrane permeation is a promising strategy for tissue-selective drug delivery. We investigated the pH-dependent interactions of designed cyclic peptides bearing noncanonical amino acids of long acidic side chains with lipid membranes, including surface binding, insertion, and translocation across the membrane. As the length of the side chain of acidic amino acid increased, the binding affinity of the peptides to phosphatidylcholine bilayer surfaces decreased, while the pH for the 50% insertion of the peptides into the bilayers increased. The pH for membrane permeation of the peptides increased with the side chain length, resulting in specific membrane permeation at pH ∼6.5. The longer side chain of acidic amino acids improved the maximum rate of membrane permeation at low pH, where both entropic and enthalpic contributions affected the permeation. Our peptide also showed intracellular delivery of cargo molecules into living cells in a pH-dependent manner.
开发具有 pH 敏感性膜通透性的环肽是组织选择性药物传递的一种很有前途的策略。我们研究了带有非典型长酸性侧链氨基酸的设计环肽与脂质膜之间的 pH 依赖性相互作用，包括表面结合、插入和跨膜转运。随着酸性氨基酸侧链长度的增加，肽与磷脂双层表面的结合亲和力降低，而肽插入双层的 pH 值增加到 50%。肽的膜通透性的 pH 值随侧链长度的增加而增加，导致在 pH ∼6.5 时具有特异性的膜通透性。酸性氨基酸的长侧链提高了低 pH 值下膜通透性的最大速率，其中熵和焓贡献都影响了通透性。我们的肽还表现出货物分子在 pH 依赖性方式下递送到活细胞内。
