Akhmadishina Rezeda A, Garifullin Ruslan, Petrova Natalia V, Kamalov Marat I, Abdullin Timur I
Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia.
Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University, Ankara, Turkey.
Front Pharmacol. 2018 Feb 19;9:115. doi: 10.3389/fphar.2018.00115. eCollection 2018.
Although delocalized lipophilic cations have been identified as effective cellular and mitochondrial carriers for a range of natural and synthetic drug molecules, little is known about their effects on pharmacological properties of peptides. The effect of triphenylphosphonium (TPP) cation on bioactivity of antioxidant tetrapeptides based on the model opioid YRFK motif was studied. Two tetrapeptide variants with L-arginine (YRFK) and D-arginine (YrFK) were synthesized and coupled with carboxyethyl-TPP (TPP-3) and carboxypentyl-TPP (TPP-6) units. The TPP moiety noticeably promoted YRFK cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on conformational variants of the tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas decreased reactivity was revealed for both YrFK and its TPP derivative. The starting motifs and modified oligopeptides, especially the TPP-6 derivatives, suppressed acute oxidative stress in neuronal PC-12 cells during a brief exposure similarly with glutathione. The effect of oligopeptides was compared upon culturing of PC-12 cells with CoCl, L-glutamic acid, or menadione to mimic physiologically relevant oxidative states. The cytoprotective activity of oligopeptides significantly depended on the type of oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of the unmodified motifs. The protease-resistant TPP-modified YrFK showed the highest activity when administered 24 h prior to the cell damage. Our results suggest that the TPP cation can be used as a modifier for small therapeutic peptides to improve their pharmacokinetic and pharmacological properties.
尽管离域亲脂性阳离子已被确认为一系列天然和合成药物分子的有效细胞和线粒体载体，但关于它们对肽类药理性质的影响却知之甚少。研究了三苯基鏻（TPP）阳离子对基于阿片样物质YRFK基序模型的抗氧化四肽生物活性的影响。合成了两种分别含有L-精氨酸（YRFK）和D-精氨酸（YrFK）的四肽变体，并与羧乙基-TPP（TPP-3）和羧戊基-TPP（TPP-6）单元偶联。TPP部分显著促进了胰蛋白酶对YRFK的切割，但有效防止了更具抗性的YrFK的消化，这分别归因于TPP阳离子对四肽基序构象变体的结构组织和屏蔽作用。在类芬顿反应模型中，TPP部分增强了修饰后的YRFK的自由基清除活性，而YrFK及其TPP衍生物的反应活性均降低。起始基序和修饰后的寡肽，尤其是TPP-6衍生物，在短暂暴露期间对神经元PC-12细胞中的急性氧化应激具有与谷胱甘肽类似的抑制作用。在用氯化钴、L-谷氨酸或甲萘醌培养PC-12细胞以模拟生理相关氧化状态时，比较了寡肽的作用。寡肽的细胞保护活性显著取决于氧化因子的类型、处理顺序和肽结构。TPP修饰的寡肽具有显著的细胞保护作用，超过了未修饰的基序。蛋白酶抗性的TPP修饰的YrFK在细胞损伤前24小时给药时显示出最高活性。我们的结果表明，TPP阳离子可作为小治疗肽的修饰剂，以改善其药代动力学和药理性质。
