Department of Chemistry, Chemical Biology, and Biomedical Engineering, Stevens Institute of Technology, Hoboken, New Jersey 07030, USA.
J Pharm Sci. 2012 Apr;101(4):1508-17. doi: 10.1002/jps.23043. Epub 2012 Jan 6.
Lytic peptides are a group of membrane-acting peptides, which have excellent activity to drug-resistant cells. In this study, the stability and tumor selectivity of newly designed pH-activated lytic peptides were studied. We found that despite varied secondary structures, pH-induced structure changes could not be directly linked to the activity and pH sensitivity of peptides. On the contrary, formation of aggregates had great impacts on peptide binding and insertion into the lipid bilayer of cell membrane. It was found that the pH controlled peptide aggregation and dissolution was responsible for the pH-dependent membrane lysis activity of peptides. One peptide (PTP-7c) formed stable amyloid fibrils, which did not completely dissolve under acidic conditions. As a result, PTP-7c had the lowest membrane lysis and cell killing activities among tested lytic peptides. As solid tumors have consistently low extracellular pHs, peptides with acid-activation features showed improved selectivity to cancer cells. In addition, self-assembled lytic peptides were found to become more stable and showed dramatically increased half lives (up to 11 h) in human plasma. These new lytic peptides with good stability and acid-activated cell lysis activity will have wide biomedical applications especially for the treatment of cancers in which drug resistance has developed.
溶细胞肽是一组作用于膜的肽，对耐药细胞具有极好的活性。在这项研究中，研究了新设计的 pH 激活溶细胞肽的稳定性和肿瘤选择性。我们发现，尽管二级结构不同，但 pH 诱导的结构变化不能直接与肽的活性和 pH 敏感性相关。相反，聚集物的形成对肽结合和插入细胞膜脂质双层有很大的影响。结果发现，pH 控制肽的聚集和解离是肽依赖 pH 的膜裂解活性的原因。一种肽（PTP-7c）形成稳定的淀粉样纤维，在酸性条件下不能完全溶解。因此，PTP-7c 在测试的溶细胞肽中具有最低的膜裂解和细胞杀伤活性。由于实体瘤的细胞外 pH 值持续较低，具有酸激活特性的肽对癌细胞表现出更好的选择性。此外，自组装的溶细胞肽在人血浆中变得更加稳定，半衰期显著增加（长达 11 小时）。这些具有良好稳定性和酸激活细胞裂解活性的新型溶细胞肽将具有广泛的生物医学应用，特别是用于治疗已经产生耐药性的癌症。
