Chen Long, Liang Jun F
College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China; Department of Chemistry, Chemical Biology, and Biomedical Engineering, Charles V. Schaefer School of Engineering and Sciences, Stevens Institute of Technology, Hoboken, NJ, 07030, USA.
Chem Biol Drug Des. 2015 Feb;85(2):208-15. doi: 10.1111/cbdd.12374. Epub 2014 Jul 7.
Glycolytic metabolism of cells produces protons that are removed from the cytosol by transport proteins to create a pH difference between the adjacent bulk solution and the cell membrane surface. Therefore, tissue cells have distinct surface pHs because of varied glycocalyx and proton production capability. In this study, we proved the role of cell surface pH in peptide-cell interaction and peptide activation using lytic peptides with pH-dependent activity as probes. Properly, selected peptides could sense the specific pH zones on cells and thus demonstrated varied activity to tissue cells with different surface pHs. For a specific cell, the activity of pH-sensitive peptides changed accordingly as the cell surface pH was tuned up or down by proton channel regulators. Mechanistic studies revealed that cell surface pH directly affected peptide insertion into membranes by altering the secondary structure and aggregation status of membrane-bound pH-sensitive peptides. A pH-sensitive lytic peptide-designed based on the cell surface pH difference between a normal-cancer cell pair showed good selectivity to cancer cells. Therefore, cell surface pHs may present new opportunities to design therapeutic peptides with high cell specificity and selectivity.
细胞的糖酵解代谢产生质子，这些质子通过转运蛋白从细胞质中移除，从而在相邻的本体溶液和细胞膜表面之间产生pH差异。因此，由于糖萼和质子产生能力的不同，组织细胞具有不同的表面pH值。在本研究中，我们以具有pH依赖性活性的裂解肽为探针，证明了细胞表面pH在肽-细胞相互作用和肽激活中的作用。适当选择的肽可以感知细胞上的特定pH区域，从而对具有不同表面pH值的组织细胞表现出不同的活性。对于特定的细胞，当通过质子通道调节剂上调或下调细胞表面pH值时，pH敏感肽的活性也会相应改变。机理研究表明，细胞表面pH通过改变膜结合pH敏感肽的二级结构和聚集状态，直接影响肽插入膜的过程。基于正常细胞与癌细胞对之间的细胞表面pH差异设计的pH敏感裂解肽对癌细胞表现出良好的选择性。因此，细胞表面pH值可能为设计具有高细胞特异性和选择性的治疗性肽提供新的机会。
