Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 이은규 | - |
dc.date.accessioned | 2020-01-28T02:49:59Z | - |
dc.date.available | 2020-01-28T02:49:59Z | - |
dc.date.issued | 2019-12 | - |
dc.identifier.citation | JOURNAL OF BIOTECHNOLOGY, v. 306, Page. 89-96 | en_US |
dc.identifier.issn | 0168-1656 | - |
dc.identifier.issn | 1873-4863 | - |
dc.identifier.uri | https://www.sciencedirect.com/science/article/pii/S0168165619308806 | - |
dc.identifier.uri | https://repository.hanyang.ac.kr/handle/20.500.11754/122262 | - |
dc.description.abstract | Exenatide, a synthetic version of exendin-4, is a glucagon-like peptide-1 receptor agonist (GLP-1RA) used for treating diabetes, but its relatively short half-life is a major disadvantage. In this study, we attempted residue-specific mono-PEGylation to the middle of the amino acid backbone to extend its in vivo half-life. Exenatide was point-mutated from Lys to Cys at the 12th residue to yield a variant (K12C), and PEG-maleimide of varying molecular weights (MW) (5, 10, 20, 40 kD) was site-specifically conjugated to yield a mono-PEGylate with branched T-shape molecular structure. In another approach, we conjugated a bis-maleimide PEG (10 kD) to the middle of two K12Cs to yield an H-shape homodimer PEGylate In vitro bioactivity assays indicated that: (1) PEGylates conjugated with higher MW PEG lead to stronger receptor binding, (2) the branched form was superior to the linear configuration in the binding, and (3) both T-shape and H-shape mono-PEGylates demonstrated better potency than the native exenatide, evidenced by lower EC50. Db/db mouse experiments to evaluate in vivo hypoglycemic activity indicated that: (1) all mono-PEGylates resulted in improved glucose tolerance compared to the native exenatide, (2) the homodimer PEGylate demonstrated much stronger hypoglycemic activity, especially during the initial period, and (3) the H-shape and T-shape mono-PEGylates (40 kD) maintained hypoglycemia for up to ca. 168 and 140 h, representing approximately 12- and 14-fold increase, respectively, compared with the native exenatide. Our findings suggest that the exenatide mono-PEGylates in unclassical molecular structures can improve in vivo pharmacokinetics properties. | en_US |
dc.description.sponsorship | This work was supported by a National Research Foundation (NRF) of Korea grant funded by the Korean government (MSIP) (No.2014R1A2A2A03004266). | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | ELSEVIER SCIENCE BV | en_US |
dc.subject | Exenatideanalogs | en_US |
dc.subject | Mono-PEGylation | en_US |
dc.subject | Homodimer PEGylate | en_US |
dc.subject | Long-acting peptides | en_US |
dc.subject | Hypoglycemic efficacy | en_US |
dc.subject | Half-life | en_US |
dc.title | Mono-PEGylates of exenatide in branched and dimeric structures can improve in vivo stability and hypoglycemic bioactivity | en_US |
dc.type | Article | en_US |
dc.relation.volume | 306 | - |
dc.identifier.doi | 10.1016/j.jbiotec.2019.09.016 | - |
dc.relation.page | 89-96 | - |
dc.relation.journal | JOURNAL OF BIOTECHNOLOGY | - |
dc.contributor.googleauthor | Nguyen, Ngoc-Thanh Thi | - |
dc.contributor.googleauthor | Jung, Sujin | - |
dc.contributor.googleauthor | Lee, Seung Hwan | - |
dc.contributor.googleauthor | Bae, Ok Nam | - |
dc.contributor.googleauthor | Lee, E. K. | - |
dc.relation.code | 2019003286 | - |
dc.sector.campus | E | - |
dc.sector.daehak | COLLEGE OF ENGINEERING SCIENCES[E] | - |
dc.sector.department | DEPARTMENT OF BIONANO ENGINEERING | - |
dc.identifier.pid | eklee | - |
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