Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Julius-von-Sachs Institute, Department for Molecular Plant Physiology and Biophysics, University of Würzburg, Julius-von-Sachs Platz 2, 97082 Würzburg, Germany.
J Control Release. 2018 Jun 10;279:17-28. doi: 10.1016/j.jconrel.2018.04.009. Epub 2018 Apr 7.
PEGylation of protein ligands, the attachment of polyethylene glycol (PEG) polymers to a therapeutic protein, increases therapeutics' half-life but frequently comes at the cost of reduced bioactivity. We are now presenting a bioinspired strategy leading out of this dilemma. To this end, we selected a position within insulin-like growth factor I (IGF-I) for decoration with a PEG-modified protease-sensitive peptide linker (PSL) using a combination of enzymatic and chemical bioorthogonal coupling strategies. The PSL sequence responded to matrix metalloproteinases (MMP) to provide a targeted release in diseased tissue. The IGF-PSL-PEG conjugate had different binding protein affinity, cell proliferation, and endocytosis patterns as compared to the wild type. Exposure of the conjugate to elevated levels of activated MMPs, as present in inflamed tissues, fully reestablished the wild type properties through effective PSL cleavage. In conclusion, this bioinspired approach provided a blueprint for PEGylated therapeutics combining the pharmacokinetic advantages of PEGylation, while locally restoring the full suite of biological potential of therapeutics.
蛋白质配体的聚乙二醇化，即将聚乙二醇（PEG）聚合物连接到治疗性蛋白质上，会增加治疗剂的半衰期，但常常会降低其生物活性。我们现在提出了一种从这个困境中走出来的仿生策略。为此，我们选择了胰岛素样生长因子 I（IGF-I）中的一个位置，使用酶和化学生物正交偶联策略的组合，用 PEG 修饰的蛋白酶敏感肽接头（PSL）对其进行修饰。PSL 序列对基质金属蛋白酶（MMP）做出响应，在病变组织中提供靶向释放。与野生型相比，IGF-PSL-PEG 缀合物具有不同的结合蛋白亲和力、细胞增殖和内吞作用模式。将该缀合物暴露于炎症组织中存在的高水平激活的 MMP 下，通过有效的 PSL 切割可完全恢复野生型特性。总之，这种仿生方法为聚乙二醇化治疗剂提供了蓝图，结合了聚乙二醇化的药代动力学优势，同时局部恢复了治疗剂的全套生物学潜力。
