Self-Assembly PEGylation Retaining Activity (SPRA) Technology via a Host–Guest Interaction Surpassing Conventional PEGylation Methods of Proteins

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• 作者：Tatsunori Hirotsu ; Taishi Higashi ; Irhan Ibrahim Abu Hashim ; Shogo Misumi ; Koki Wada ; Keiichi Motoyama ; Hidetoshi Arima
• 刊名：Molecular Pharmaceutics
• 出版年：2017
• 出版时间：February 6, 2017
• 年：2017
• 卷：14
• 期：2
• 页码：368-376
• 全文大小：574K
• ISSN：1543-8392

文摘

Polyethylene glycol (PEG) modification (PEGylation) is one of the best approaches to improve the stabilities and blood half-lives of protein drugs; however, PEGylation dramatically reduces the bioactivities of protein drugs. Here, we present “self-assembly PEGylation retaining activity” (SPRA) technology via a host–guest interaction between PEGylated β-cyclodextrin (PEG-β-CyD) and adamantane-appended (Ad) proteins. PEG-β-CyD formed stable complexes with Ad-insulin and Ad-lysozyme to yield SPRA-insulin and SPRA-lysozyme, respectively. Both SPRA-proteins showed high stability against heat and trypsin digest, comparable with that of covalently PEGylated protein equivalents. Importantly, the SPRA-lysozyme possessed ca. 100% lytic activity, whereas the activity of the covalently PEGylated lysozyme was ca. 23%. Additionally, SPRA-insulin provided a prolonged and peakless blood glucose profile when compared with insulin glargine. It also showed no loss of activity. In contrast, the covalently PEGylated insulin showed a negligible hypoglycemic effect. These findings indicate that SPRA technology has potential as a generic method, surpassing conventional PEGylation methods for proteins.