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
- Authors
- Kim, Insoo; Kim, Tae Hyung; Ma, Kyungwan; Park, Eun-Seok; Oh, Kyung Taek; Lee, Eun Seong; Lee, Kang Choon; Youn, Yu Seok
- Issue Date
- Apr-2011
- Publisher
- ELSEVIER SCIENCE BV
- Keywords
- Exendin-4; 4-arm PEG; Albumin binding; PEGylation; Type 2 diabetes
- Citation
- REGULATORY PEPTIDES, v.167, no.2-3, pp 239 - 245
- Pages
- 7
- Journal Title
- REGULATORY PEPTIDES
- Volume
- 167
- Number
- 2-3
- Start Page
- 239
- End Page
- 245
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/21603
- DOI
- 10.1016/j.regpep.2011.02.008
- ISSN
- 0167-0115
1873-1686
- 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 (169 kDa) than actual (28.9 kDa) by size-exclusion chromatography and acceptable binding capability (similar to 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 18.6 h at a dose 250 nmol/kg as compared with exendin-4 (8.7 h). 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. (C) 2011 Elsevier B.V. All rights reserved.
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