期刊
PEPTIDES
卷 52, 期 -, 页码 11-18出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.peptides.2013.11.012
关键词
PEGylation; Porcine glucagon-like peptide-2; Ion-exchange chromatography; Dextran sulfate sodium; Colitis
资金
- earmarked fund for modern Agro-industry Technology Research System [CARS-36]
- National Natural Science Funds of China [C170105/31101724]
The rapid degradation of porcine glucagon-like peptide-2 (pGLP-2) by the enzyme dipeptidyl peptidaseIV (DPP-IV) is the main impediment in the development of pGLP-2 as a potential therapeutic agent for intestinal dysfunction and damage. In this study, one mono-modified Lys30-polyethylene glycol (PEG)pGLP-2 was prepared using mPEG-succinimidyl propionate. To determine the optimized condition for PEGylation, the reactions were monitored by RP-HPLC and MALDI-TOF-MS. Stability was tested in purified DPP-IV in vitro. In vivo, the protective effects for colonic injury were measured in dextran sulfate sodium (DSS)-induced colitis in mice. The monoPEGylated products reached the maximum yield at 4:1 ratio of mPEG(5k)-SPA to pGLP-2. An effective method of successfully separating PEGylated pGLP-2 from mPEG-SPA(5kD) using CM Sepharose Fast Flow resin was established. The half-life of Lys(30)-PEG-pGLP-2 was 16-fold longer than that of pGLP-2 in DPP-IV. The DSS mice exhibited marked weight loss), which was significantly reduced by Lys(30)-PEG-pGLP-2 therapy. DSS treatment significantly increased colonic damage score, which was significantly reduced by administration of Lys(30)-PEG-pGLP-2 in DSS-mice. DSS-induced colitis clearly induced Myeloperoxidase activity in the colon, which was significantly reduced by treatments with 3% DSS-pGLP-2 or 3% DSS-PEG-pGLP-2. These results showed that site-specific Lys(30-)PEG-GLP-2 was resistant to degradation and reduced the severity of colonic injury in murine colitis. The enhanced biological potency of this product highlighted its potential as a therapeutic agent for intestinal diseases. (C) 2013 Elsevier Inc. All rights reserved.
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