Reshetnyak Yana K, Andreev Oleg A, Lehnert Ursula, Engelman Donald M
Department of Molecular Biophysics and Biochemistry, Yale University, P.O. Box 208114, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6460-5. doi: 10.1073/pnas.0601463103. Epub 2006 Apr 11.
We have previously observed the spontaneous, pH-dependent insertion of a water-soluble peptide to form a helix across lipid bilayers [Hunt, J. F., Rath, P., Rothschild, K. J. & Engelman, D. M. (1997) Biochemistry 36, 15177-15192]. We now use a related peptide, pH (low) insertion peptide, to translocate cargo molecules attached to its C terminus across the plasma membranes of living cells. Translocation is selective for low pH, and various types of cargo molecules attached by disulfides can be released by reduction in the cytoplasm, including peptide nucleic acids, a cyclic peptide (phalloidin), and organic compounds. Because a high extracellular acidity is characteristic of a variety of pathological conditions (such as tumors, infarcts, stroke-afflicted tissue, atherosclerotic lesions, sites of inflammation or infection, or damaged tissue resulting from trauma) or might be created artificially, pH (low) insertion peptide may prove a useful tool for selective delivery of agents for drug therapy, diagnostic imaging, genetic control, or cell regulation.
我们之前观察到一种水溶性肽能自发地、依赖pH地插入脂质双层以形成跨膜螺旋[亨特，J.F.，拉特，P.，罗斯柴尔德，K.J.和恩格尔曼，D.M.（1997年）《生物化学》36卷，第15177 - 15192页]。我们现在使用一种相关肽，即低pH插入肽，来使与其C末端相连的货物分子穿过活细胞的质膜。转运对低pH具有选择性，通过二硫键连接的各种类型的货物分子可在细胞质中通过还原作用释放，包括肽核酸、一种环肽（鬼笔环肽）和有机化合物。由于细胞外高酸度是多种病理状况（如肿瘤、梗死、中风损伤组织、动脉粥样硬化病变、炎症或感染部位或创伤导致的受损组织）的特征，或者可能被人为制造，低pH插入肽可能证明是一种用于选择性递送药物治疗、诊断成像、基因控制或细胞调节试剂的有用工具。
