Replacement of the C-terminal Trp-cage of exendin-4 with a fatty acid improves therapeutic utility
DC Field | Value | Language |
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dc.contributor.author | Lee, Jung Gi | - |
dc.contributor.author | Ryu, Jae Ha | - |
dc.contributor.author | Kim, Seon-Myung | - |
dc.contributor.author | Park, Moon-Young | - |
dc.contributor.author | Kim, San-Ho | - |
dc.contributor.author | Shin, Young G. | - |
dc.contributor.author | Sohn, Jong-Woo | - |
dc.contributor.author | Kim, Ha Hyung | - |
dc.contributor.author | Park, Zee-Yong | - |
dc.contributor.author | Seong, Jae Young | - |
dc.contributor.author | Kim, Jae Il | - |
dc.date.accessioned | 2021-09-02T11:43:58Z | - |
dc.date.available | 2021-09-02T11:43:58Z | - |
dc.date.created | 2021-06-19 | - |
dc.date.issued | 2018-05 | - |
dc.identifier.issn | 0006-2952 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/75607 | - |
dc.description.abstract | Exendin-4, a 39 amino acid peptide isolated from the saliva of the Gila monster, plays an important role in regulating glucose homeostasis, and is used clinically for the treatment of type 2 diabetes. Exendin-4 shares 53% sequence identity with the incretin hormone glucagon-like peptide 1 (GLP-1) but, unlike GLP-1, is highly resistant to proteolytic enzymes such as dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase 24.11 (NEP 24.11). Herein, we focused on the structure and function of the C-terminal Trp-cage of exendin-4, and suggest that it may be structurally required for resistance to proteolysis by NEP 24.11. Using a series of substitutions and truncations of the C-terminal Trp-cage, we found that residues 1-33, including the N-terminal and helical regions of wild-type (WT) exendin-4, is the minimum motif required for both high peptidase resistance and potent activity toward the GLP-1 receptor comparable to WT exendin-4. To improve the therapeutic utility of C-terminally truncated exendin-4, we incorporated various fatty acids into exendin-4(1-33) in which Ser(33) was substituted with Lys for acylation. Exendin-4(1-32)K-capric acid exhibited the most well balanced activity, with much improved therapeutic utility for regulating blood glucose and body weight relative to WT exendin-4. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | PERGAMON-ELSEVIER SCIENCE LTD | - |
dc.subject | GLUCAGON-LIKE PEPTIDE-1 | - |
dc.subject | TYPE-2 DIABETES-MELLITUS | - |
dc.subject | INCRETIN MIMETICS | - |
dc.subject | GLP-1 RECEPTOR | - |
dc.subject | EXTRACELLULAR DOMAIN | - |
dc.subject | CONJUGATED EXENDIN-4 | - |
dc.subject | EXTENDED-RELEASE | - |
dc.subject | IV INHIBITORS | - |
dc.subject | IN-VIVO | - |
dc.subject | ALBUMIN | - |
dc.title | Replacement of the C-terminal Trp-cage of exendin-4 with a fatty acid improves therapeutic utility | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Seong, Jae Young | - |
dc.identifier.doi | 10.1016/j.bcp.2018.03.004 | - |
dc.identifier.scopusid | 2-s2.0-85043355234 | - |
dc.identifier.wosid | 000431099400007 | - |
dc.identifier.bibliographicCitation | BIOCHEMICAL PHARMACOLOGY, v.151, pp.59 - 68 | - |
dc.relation.isPartOf | BIOCHEMICAL PHARMACOLOGY | - |
dc.citation.title | BIOCHEMICAL PHARMACOLOGY | - |
dc.citation.volume | 151 | - |
dc.citation.startPage | 59 | - |
dc.citation.endPage | 68 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Pharmacology & Pharmacy | - |
dc.relation.journalWebOfScienceCategory | Pharmacology & Pharmacy | - |
dc.subject.keywordPlus | GLUCAGON-LIKE PEPTIDE-1 | - |
dc.subject.keywordPlus | TYPE-2 DIABETES-MELLITUS | - |
dc.subject.keywordPlus | INCRETIN MIMETICS | - |
dc.subject.keywordPlus | GLP-1 RECEPTOR | - |
dc.subject.keywordPlus | EXTRACELLULAR DOMAIN | - |
dc.subject.keywordPlus | CONJUGATED EXENDIN-4 | - |
dc.subject.keywordPlus | EXTENDED-RELEASE | - |
dc.subject.keywordPlus | IV INHIBITORS | - |
dc.subject.keywordPlus | IN-VIVO | - |
dc.subject.keywordPlus | ALBUMIN | - |
dc.subject.keywordAuthor | Diabetes | - |
dc.subject.keywordAuthor | Exendin-4 | - |
dc.subject.keywordAuthor | Fatty acid | - |
dc.subject.keywordAuthor | GLP-1 receptor | - |
dc.subject.keywordAuthor | Neutral endopeptidase 24.11 | - |
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