title: A 4-arm polyethylene glycol derivative conjugated with exendin-4 peptide and palmitylamine having dual-function of size-increase and albumin-binding for long hypoglycemic action.
abstract: PEGylation and albumin binding are viewed as the most effective ways of prolonging the lifespans of short-lived peptides by delaying renal filtration. Here, we describe a derivative of exendin-4 with pharmaceutical benefits produced using both techniques. This exendin-4 derivative is based on a 4-arm PEG(20k) conjugated with two exendin-4s and two palmitylamines on its arms. PEG and palmitylamine were chosen to increase molecular size and bind to albumin, respectively. This derivative (Ex4-PEG-C16) was found to have larger molecular size (169kDa) than actual (28.9kDa) by size-exclusion chromatography and acceptable binding capability (~90%) to immobilized-albumin. Although the receptor-binding of Ex4-PEG-C16 to RIN-m5F cells was significantly lower than that of exendin-4, its acute anti-hyperglycemic efficacy was equivalent to that of exendin-4 in type 2 diabetic db/db mice. Furthermore, Ex4-PEG-C16 displayed a >6-fold increase in AUC and circulating t(1/2)vs. exendin-4. Due to this improvement, its hypoglycemic duration was greatly increased to 18.6h at a dose 250nmol/kg as compared with exendin-4 (8.7h). Our results show that the combined technique of PEGylation and albumin binding was effective when applied to exendin-4. We believe that this exendin-4 derivative has considerable pharmaceutical potential as a novel type 2 anti-diabetic systemic treatment.
authors.affiliation: College of Pharmacy, Pusan National University, Jangjun-dong, Geumjeong-gu, Busan 609-735, Republic of Korea.
authors.forename: Insoo
authors.initials: I
authors.lastname: Kim
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.forename: Kyungwan
authors.initials: K
authors.lastname: Ma
authors.forename: Eun-Seok
authors.initials: ES
authors.lastname: Park
authors.forename: Kyung Taek
authors.initials: KT
authors.lastname: Oh
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000494:pharmacology; D014688:Venoms / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000418:Albumins; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D011092:Polyethylene Glycols; D000077270:Exenatide