Site-specific PEGylated Exendin-4 modified with a high molecular weight trimeric PEG reduces steric hindrance and increases type 2 antidiabetic therapeutic effects

Title
Site-specific PEGylated Exendin-4 modified with a high molecular weight trimeric PEG reduces steric hindrance and increases type 2 antidiabetic therapeutic effects
Authors
최기영김태형Hai Hua Jiang임성묵윤유석이슬기Xiaoyuan Chen변영로이강춘
Issue Date
2012-11
Publisher
Bioconjugate chemistry
Citation
VOL 23, NO 11-2220
Abstract
The purpose of this study was to optimize an Exendin-4 (Ex4-Cys) site-specific PEGylation method with a high-molecular-weight trimeric PEG. Here, we describe the preparation of C-terminal specific PEGylated Ex4-Cys (C40-tPEG-Ex4-Cys), which was performed using cysteine and amine residue specific coupling reactions between Ex4-Cys and activated trimeric PEG. The C40-PEG-Ex4-Cys was obtained at high yields (similar to 83%) and characterized by MALDI-TOF mass spectrometry. The receptor binding affinity of C40-PEG(5K)-Ex4-Cys was 3.5-fold higher than that of N-terminal PEGylated Ex4-Cys (N-ter-PEG(5K)-Ex4-Cy5), and receptor binding by the trimeric PEG (tPEG; 23, 50 kDa) adduct was much higher than that of branched PEG (20 kDa). Furthermore, C40-tPEG(50K)-Ex4-Cys was found to have greater blood circulating t(1/2) and AUC(inf) values than native Ex4-Cys by 7.53- and 45.61-fold, respectively. Accordingly; its hypoglycemic duration was much greater at 59.2 h than that of native Ex4-Cys at 7.3 h, with a dose of 25 nM/kg. The results of this study; show that C-terminal specific PEGylation using trimeric PEG is effective when applied to Ex4-Cys and suggest that C40-tPEG(50K)-Ex4-Cys has considerable potential as a type 2 antidiabetic agent.
URI
http://pubs.kist.re.kr/handle/201004/69378
ISSN
1043-1802
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KIST Publication > Article
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