Synthesis and Evaluation of Human Serum Albumin-Modified Exendin-4 Conjugate via Heterobifunctional Polyethylene Glycol Linkage with Protracted Hypoglycemic Efficacy
DC Field | Value | Language |
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dc.contributor.author | Kim, Insoo | - |
dc.contributor.author | Kim, Tae Hyung | - |
dc.contributor.author | Ma, Kyungwan | - |
dc.contributor.author | Lee, Eun Seong | - |
dc.contributor.author | Kim, Dongin | - |
dc.contributor.author | Oh, Kyung Taek | - |
dc.contributor.author | Lee, Don Haeng | - |
dc.contributor.author | Lee, Kang Choon | - |
dc.contributor.author | Youn, Yu Seok | - |
dc.date.available | 2019-05-30T00:57:08Z | - |
dc.date.issued | 2010-08 | - |
dc.identifier.issn | 1043-1802 | - |
dc.identifier.issn | 1520-4812 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/22308 | - |
dc.description.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. | - |
dc.format.extent | 7 | - |
dc.language | 영어 | - |
dc.language.iso | ENG | - |
dc.publisher | AMER CHEMICAL SOC | - |
dc.title | Synthesis and Evaluation of Human Serum Albumin-Modified Exendin-4 Conjugate via Heterobifunctional Polyethylene Glycol Linkage with Protracted Hypoglycemic Efficacy | - |
dc.type | Article | - |
dc.identifier.doi | 10.1021/bc100143c | - |
dc.identifier.bibliographicCitation | BIOCONJUGATE CHEMISTRY, v.21, no.8, pp 1513 - 1519 | - |
dc.description.isOpenAccess | N | - |
dc.identifier.wosid | 000280918900017 | - |
dc.identifier.scopusid | 2-s2.0-77955830619 | - |
dc.citation.endPage | 1519 | - |
dc.citation.number | 8 | - |
dc.citation.startPage | 1513 | - |
dc.citation.title | BIOCONJUGATE CHEMISTRY | - |
dc.citation.volume | 21 | - |
dc.type.docType | Article | - |
dc.publisher.location | 미국 | - |
dc.subject.keywordPlus | GLUCAGON-LIKE PEPTIDE-1 | - |
dc.subject.keywordPlus | GLUCOSE-HOMEOSTASIS | - |
dc.subject.keywordPlus | IN-VIVO | - |
dc.subject.keywordPlus | INSULIN | - |
dc.subject.keywordPlus | STABILITY | - |
dc.subject.keywordPlus | DELIVERY | - |
dc.subject.keywordPlus | PROTEIN | - |
dc.subject.keywordPlus | RATS | - |
dc.relation.journalResearchArea | Biochemistry & Molecular Biology | - |
dc.relation.journalResearchArea | Chemistry | - |
dc.relation.journalWebOfScienceCategory | Biochemical Research Methods | - |
dc.relation.journalWebOfScienceCategory | Biochemistry & Molecular Biology | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Multidisciplinary | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Organic | - |
dc.description.journalRegisteredClass | sci | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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