Synthesis and Evaluation of Human Serum Albumin-Modified Exendin-4 Conjugate via Heterobifunctional Polyethylene Glycol Linkage with Protracted Hypoglycemic Efficacy
- Authors
- Kim, Insoo; Kim, Tae Hyung; Ma, Kyungwan; Lee, Eun Seong; Kim, Dongin; Oh, Kyung Taek; Lee, Don Haeng; Lee, Kang Choon; Youn, Yu Seok
- Issue Date
- Aug-2010
- Publisher
- AMER CHEMICAL SOC
- Citation
- BIOCONJUGATE CHEMISTRY, v.21, no.8, pp 1513 - 1519
- Pages
- 7
- Journal Title
- BIOCONJUGATE CHEMISTRY
- Volume
- 21
- Number
- 8
- Start Page
- 1513
- End Page
- 1519
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/22308
- DOI
- 10.1021/bc100143c
- ISSN
- 1043-1802
1520-4812
- Abstract
- Albumin conjugation is considered to be one of the most effective means of protracting the short in vivo lifespans of peptides and proteins. Here, we present a new long-acting antidiabetic exendin-4 conjugate linked with human serum albumin (HSA) via polyethylene glycol (PEG). As a first step toward synthesizing this conjugate, three artificial sulfhydryl groups were introduced in HSA using 2-iminothiolane at pH 8.0. This thiolated HSA was further reacted with the monomer fraction of exendin-4 (6 equiv) conjugated with maleimide-PEG(5k)-N-hydroxysuccinimide (MAL-PEG(5k)-NHS) for 3 h. Because of the presence of PEG molecules, the resulting conjugate (HSA-PEG-Ex4) was found to have a greater apparent molecular weight and a larger particle size (ca. 195 kDa and 9.48 +/- 0.74 nm) than those of HSA-exendin-4 without the PEG linker (HSA-Ex4, ca. 84.3 kDa and 7.77 +/- 0.98 nm). Although the receptor binding affinity of HSA-PEG-Ex4 on RIN-m5F cells was significantly lower than that of Ex4, its antihyperglycemic efficacy was slightly higher than that of Ex-4 and HSA-Ex4 in type 2 diabetic db/db mice. Furthermore, HSA-PEG-Ex4 had greater circulating t(1/2) and AUC(inf) values than HSA-Ex and native exendin-4 by 2.1- and 10.3-fold, respectively. Accordingly, its hypoglycemic duration was greatly increased to 31.0 h at a dose of 250 nmol/kg vs that of native Ex4 (7.0 h). Results show that the HSA-PEG-Ex4 conjugate produced has distinct advantages over HSA-Ex4 without PEG. We believe that this exendin-4 derivative, which has the merits of albumin conjugation and PEGylation, has considerable potential as a novel type 2 antidiabetic agent.
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