Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Bioconjug Chem. 2013 Jun 19;24(6):915-25. doi: 10.1021/bc300603k. Epub 2013 May 9.
Fibroblast growth factor 21 (FGF21) is involved in regulating energy metabolism, and it has shown significant promise as a treatment for type II diabetes; however, the native protein has a very short circulating half-life necessitating frequent injections to maintain a physiological effect. Polyethylene glycol (PEG) conjugation to proteins has been used as a method for extending the circulating half-life of many pharmaceutical proteins; however, PEG does carry the risk of vacuole formation, particularly in the renal tubular epithelium. Since renal vacuole formation may be particularly problematic for diabetic patients, we engineered site-directed PEGylated variants of FGF21 with sustained potency and minimized vacuole formation. This was accomplished both by probing the site of PEGylation on FGF21 as well as by examining various PEG configurations. While the site of PEGylation has a significant impact on the bioactivity of FGF21, it has only a marginal impact on vacuole formation; however, the configuration and number of PEGs conjugated to the protein has a much more profound effect on vacuologenesis.
成纤维细胞生长因子 21（FGF21）参与调节能量代谢，它作为 II 型糖尿病的治疗方法显示出巨大的潜力；然而，天然蛋白的循环半衰期非常短，需要频繁注射以维持生理效应。聚乙二醇（PEG）与蛋白质的结合已被用作延长许多药物蛋白循环半衰期的方法；然而，PEG 确实存在形成空泡的风险，特别是在肾小管上皮细胞中。由于肾空泡形成对糖尿病患者可能特别成问题，我们设计了具有持续效力和最小化空泡形成的 FGF21 定点 PEG 化变体。这是通过探测 FGF21 上的 PEG 化位点以及检查各种 PEG 构型来实现的。虽然 PEG 化位点对 FGF21 的生物活性有显著影响，但对空泡形成的影响很小；然而，与蛋白质结合的 PEG 的构型和数量对空泡发生有更深远的影响。
