Andreev Oleg A, Engelman Donald M, Reshetnyak Yana K
Department of Physics, University of Rhode Island Kingston, RI, USA.
Department of Molecular Biophysics and Biochemistry, Yale University New Haven, CT, USA.
Front Physiol. 2014 Mar 13;5:97. doi: 10.3389/fphys.2014.00097. eCollection 2014.
The discovery of the pH Low Insertion Peptides (pHLIPs®) provides an opportunity to develop imaging and drug delivery agents targeting extracellular acidity. Extracellular acidity is associated with many pathological states, such as those in cancer, ischemic stroke, neurotrauma, infection, lacerations, and others. The metabolism of cells in injured or diseased tissues often results in the acidification of the extracellular environment, so acidosis might be useful as a general marker for the imaging and treatment of diseased states if an effective targeting method can be developed. The molecular mechanism of a pHLIP peptide is based on pH-dependent membrane-associated folding. pHLIPs, being moderately hydrophobic peptides, have high affinities for cellular membranes at normal pH, but fold and insert across membranes at low pH, allowing them to sense pH at the surfaces of cells in diseased tissues, where it is the lowest. Here we discuss the main principles of pHLIP interactions with membrane lipid bilayers at neutral and low pHs, the possibility of tuning the folding and insertion pH by peptide sequence variation, and potential applications of pHLIPs for imaging, therapy and image-guided interventions.
pH低插入肽（pHLIPs®）的发现为开发针对细胞外酸度的成像和药物递送剂提供了契机。细胞外酸度与许多病理状态相关，如癌症、缺血性中风、神经创伤、感染、撕裂伤等。受损或患病组织中细胞的代谢常常导致细胞外环境酸化，因此，如果能开发出有效的靶向方法，酸中毒可能作为疾病状态成像和治疗的通用标志物。pHLIP肽的分子机制基于pH依赖性的膜相关折叠。pHLIPs作为中等疏水性肽，在正常pH下对细胞膜具有高亲和力，但在低pH下折叠并插入跨膜，使其能够在患病组织中细胞表面（此处pH最低）感知pH。在此，我们讨论pHLIP在中性和低pH下与膜脂双层相互作用的主要原理、通过肽序列变异调节折叠和插入pH的可能性，以及pHLIP在成像、治疗和图像引导干预方面的潜在应用。
