title: Self-Assembly PEGylation Retaining Activity (SPRA) Technology via a Host-Guest Interaction Surpassing Conventional PEGylation Methods of Proteins.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Hirotsu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Faculty of Pharmacy, Mansoura University , Mansoura 35516, Egypt.
authors.forename: Irhan Ibrahim
authors.initials: II
authors.lastname: Abu Hashim
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Misumi
authors.affiliation: Nihon Shokuhin Kako Co., Ltd. , 30 Tajima, Fuji, Shizuoka 417-8539, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Wada
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Hidetoshi
authors.identifier: 0000-0001-5498-4234
authors.initials: H
authors.lastname: Arima
mesh_terms: D000818:Animals; D007004:Hypoglycemic Agents / Q000737:chemistry; D007328:Insulin / Q000031:analogs & derivatives / Q000737:chemistry; D008297:Male; D009113:Muramidase / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D014357:Trypsin / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D011506:Proteins; D047392:beta-Cyclodextrins; C039441:insulin, polyethylene glycol(B1)-; D011092:Polyethylene Glycols; D009113:Muramidase; D014357:Trypsin
keywords: adamantine; cyclodextrin; polyethylene glycol; protein; supramolecular host−guest interaction