二聚翻译控制的肿瘤蛋白(dTCTP)在小鼠模型中引发多种过敏反应,并且dTCTP结合肽2(dTBP2)通过靶向dTCTP来减轻过敏性炎症。然而,基于肽的药物的有用性往往是有限的,因为它们的半衰期短,快速降解,全身给药后的清除率很高。在这项研究中,我们将dTBP2与10kDa聚乙二醇(PEG)化学缀合,以提高其治疗潜力。N-末端单PEG化dTBP2(PEG-dTBP2)通过体外生物活性测定进行表征,药代动力学研究,和体内功效。与未修饰的dTBP2相比,PEG-dTBP2在人支气管细胞中减少了10%至15%的促炎细胞因子IL-8分泌,并在小鼠中增加了约2.5倍的血浆半衰期。该研究特别证明,与dTBP2相比,PEG-dTBP2对小鼠中的卵清蛋白(OVA)诱导的气道炎症显示出更高的抑制作用。重要的是,PEG-dTBP2,以1mg/kg一次给药,显着降低了炎症细胞的迁移和支气管肺泡灌洗液中细胞因子的水平以及血清中OVA特异性IgE的水平。此外,与对照组相比,PEG-dTBP2组杯状细胞增生程度和粘液分泌程度明显减弱。这些结果表明PEG-dTBP2可以被认为是调节过敏性炎症的潜在候选药物。
Dimerized translationally controlled tumor protein (dTCTP) initiates a variety of allergic responses in mouse models and that dTCTP-binding peptide 2 (dTBP2) attenuates the allergic inflammation by targeting dTCTP. However, the usefulness of peptide-based drugs is often limited due to their short half-lives, rapid degradation, and high levels of clearance after systemic administration. In this study, we chemically conjugated dTBP2 with 10 kDa polyethylene glycol (PEG) to improve its therapeutic potential. N-terminal mono-PEGylated dTBP2 (PEG-dTBP2) was characterized by in vitro bioactivity assay, pharmacokinetics study, and in vivo efficacy. When compared to the unmodified dTBP2, PEG-dTBP2 reduced proinflammatory cytokine IL-8 secretion in human bronchial cells by 10 to 15% and increased plasma half-life by approximately 2.5-fold in mice. This study specifically demonstrated that PEG-dTBP2 shows higher inhibitory action against ovalbumin (OVA)-induced airway inflammation in mice compared to dTBP2. Importantly, PEG-dTBP2, when administered once at 1 mg/kg, significantly reduced the migration of inflammatory cells and the levels of cytokines in the bronchoalveolar lavage fluids as well as OVA-specific IgE levels in serum. In addition, the degree of goblet cell hyperplasia and mucus secretion were significantly attenuated in the PEG-dTBP2 group compared with the control group. These results suggest that PEG-dTBP2 can be considered a potential candidate drug for regulating allergic inflammation.