Molecular and Cell Institute, University Miguel Hernández (IBMC-UMH), Elche 03202, Spain.
Mar Drugs. 2013 Jul 4;11(7):2328-46. doi: 10.3390/md11072328.
Myticin C (Myt C) is a highly variable host-defense peptide (HDP) associated to the immune response in the mediterranean mussel (Mytilus galloprovincialis), which has shown to be active across species due to its strong antiviral activity against a fish rhabdovirus found in fish cells overexpressing this HDP. However, the potential antimicrobial properties of any synthetic analogue of Myt C has not yet been analysed. Thus, in this work we have synthesised the sequence of the mature peptide of Myt C variant c and analysed the structure activity relationships of its reduced (non-oxidized) form (red-MytCc). In contrast to results previously reported for oxidized isoforms of mussel myticins, red-MytCc was not active against bacteria at physiological pH and showed a moderate antiviral activity against the viral haemorrhagic septicaemia (VHS) rhabdovirus. However, its chemotactic properties remained active. Structure/function studies in neutral and acid environments by means of infrared spectroscopy indicated that the structure of red-MytCc is pH dependent, with acid media increasing its alpha-helical content. Furthermore, red-MytCc was able to efficiently aggregate artificial phospholipid membranes at low pH, as well as to inhibit the Escherichia coli growth, suggesting that this activity is attributable to its more structured form in an acidic environment. All together, these results highlight the dynamic and environmentally sensitive behavior of red-Myt C in solution, and provide important insights into Myt C structure/activity relationships and the requirements to exert its antimicrobial/immunomodulatory activities. On the other hand, the pH-dependent direct antimicrobial activity of Myt C suggests that this HDP may be a suitable template for the development of antimicrobial agents that would function selectively in specific pH environments, which are sorely needed in this "antibiotic-resistance era".
Myticin C (Myt C) 是一种高度可变的宿主防御肽 (HDP)，与地中海贻贝 (Mytilus galloprovincialis) 的免疫反应有关，由于其对鱼类细胞中过度表达这种 HDP 的鱼类弹状病毒具有很强的抗病毒活性，因此已被证明在物种间具有活性。然而，任何 Myt C 合成类似物的潜在抗菌特性尚未得到分析。因此，在这项工作中，我们合成了 Myt C 变体 c 的成熟肽序列，并分析了其还原形式（非氧化形式）（red-MytCc）的结构-活性关系。与以前报道的贻贝肌肽氧化同工型的结果相反，red-MytCc 在生理 pH 下对细菌没有活性，并且对病毒性出血性败血症 (VHS) 弹状病毒具有中等抗病毒活性。然而，它的趋化活性仍然活跃。通过红外光谱在中性和酸性环境中的结构/功能研究表明，red-MytCc 的结构依赖于 pH，酸性介质增加其α-螺旋含量。此外，red-MytCc 能够在低 pH 下有效地聚集人工磷脂膜，并抑制大肠杆菌的生长，这表明这种活性归因于其在酸性环境中的更结构化形式。总之，这些结果突出了 red-Myt C 在溶液中的动态和环境敏感行为，并为 Myt C 的结构/活性关系以及发挥其抗菌/免疫调节活性的要求提供了重要的见解。另一方面，Myt C 的 pH 依赖性直接抗菌活性表明，这种 HDP 可能是开发抗菌剂的合适模板，这些抗菌剂将在特定 pH 环境中选择性发挥作用，这在“抗生素耐药时代”是非常需要的。
