期刊
RSC ADVANCES
卷 12, 期 49, 页码 31892-31899出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2ra05872c
关键词
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资金
- Hebei Provincial Department of Human Resources and Social Security grants [C201812, C20190348, E2018100010]
- Foundation of Hebei Educational Committee [QN2019217]
- Natural Science Foundation of Hebei Province [C2020205049, H2021208001]
A method to prepare long-acting GLP-1 through glycosylation has been developed, resulting in increased in vitro half-life and enhanced glucose-stabilizing capability. Selection of the appropriate modification site is crucial for improving the therapeutic properties of the modified peptides.
In this study, an approach to prepare long-acting glucagon-like peptide 1 (GLP-1) by site-directed enzymatic glycosylation with homogeneous biantennary complex-type N-glycan has been developed. All the N-glycan-modified GLP-1 analogues preserved an unchanged secondary structure. The glycosylated GLP-1 analogues with sialyl complex-type N-glycan modified at Asn26 and Asn34 exhibited a 36.7- and 24.0-fold in vitro half-life respectively when incubated with dipeptidyl peptidase-IV (DPP-IV), and 25.0- and 13.9-fold respectively when incubated with mouse serum. Compared to native GLP-1, both glycosylated GLP-1 analogues modified at Asn34 by asialyl and sialyl N-glycan demonstrated lower maximum blood glucose levels, as well as more rapid and more persistent glucose-stabilizing capability in type 2 diabetic db/db mice. Our results indicated that the selection of an appropriate position (to avoid hindering the peptide-receptor binding) is crucial for N-glycan modification and its sialylation to improve the therapeutic properties of the modified peptides. The information learned would facilitate future design of therapeutic glycopeptides/glycoproteins with N-glycan to achieve enhanced pharmacological properties.
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