Replacement of the C-terminal Trp-cage of exendin-4 with a fatty acid improves therapeutic utility

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dc.contributor.authorLee, Jung Giko
dc.contributor.authorRyu, Jae Hako
dc.contributor.authorKim, Seon-Myungko
dc.contributor.authorPark, Moon-Youngko
dc.contributor.authorKim, San-Hoko
dc.contributor.authorShin, Young G.ko
dc.contributor.authorSohn, Jong Wooko
dc.contributor.authorKim, Ha Hyungko
dc.contributor.authorPark, Zee-Yongko
dc.contributor.authorSeong, Jae Youngko
dc.contributor.authorKim, Jae Ilko
dc.date.accessioned2018-04-24T02:15:13Z-
dc.date.available2018-04-24T02:15:13Z-
dc.date.created2018-03-23-
dc.date.created2018-03-23-
dc.date.created2018-03-23-
dc.date.issued2018-05-
dc.identifier.citationBIOCHEMICAL PHARMACOLOGY, v.151, pp.59 - 68-
dc.identifier.issn0006-2952-
dc.identifier.urihttp://hdl.handle.net/10203/241084-
dc.description.abstractExendin-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-
dc.languageEnglish-
dc.publisherPERGAMON-ELSEVIER SCIENCE LTD-
dc.subjectGLUCAGON-LIKE PEPTIDE-1-
dc.subjectTYPE-2 DIABETES-MELLITUS-
dc.subjectINCRETIN MIMETICS-
dc.subjectGLP-1 RECEPTOR-
dc.subjectEXTRACELLULAR DOMAIN-
dc.subjectCONJUGATED EXENDIN-4-
dc.subjectEXTENDED-RELEASE-
dc.subjectIV INHIBITORS-
dc.subjectIN-VIVO-
dc.subjectALBUMIN-
dc.titleReplacement of the C-terminal Trp-cage of exendin-4 with a fatty acid improves therapeutic utility-
dc.typeArticle-
dc.identifier.wosid000431099400007-
dc.identifier.scopusid2-s2.0-85043355234-
dc.type.rimsART-
dc.citation.volume151-
dc.citation.beginningpage59-
dc.citation.endingpage68-
dc.citation.publicationnameBIOCHEMICAL PHARMACOLOGY-
dc.identifier.doi10.1016/j.bcp.2018.03.004-
dc.contributor.localauthorSohn, Jong Woo-
dc.contributor.nonIdAuthorLee, Jung Gi-
dc.contributor.nonIdAuthorRyu, Jae Ha-
dc.contributor.nonIdAuthorKim, Seon-Myung-
dc.contributor.nonIdAuthorPark, Moon-Young-
dc.contributor.nonIdAuthorKim, San-Ho-
dc.contributor.nonIdAuthorShin, Young G.-
dc.contributor.nonIdAuthorKim, Ha Hyung-
dc.contributor.nonIdAuthorPark, Zee-Yong-
dc.contributor.nonIdAuthorSeong, Jae Young-
dc.contributor.nonIdAuthorKim, Jae Il-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordAuthorDiabetes-
dc.subject.keywordAuthorExendin-4-
dc.subject.keywordAuthorFatty acid-
dc.subject.keywordAuthorGLP-1 receptor-
dc.subject.keywordAuthorNeutral endopeptidase 24.11-
dc.subject.keywordPlusGLUCAGON-LIKE PEPTIDE-1-
dc.subject.keywordPlusTYPE-2 DIABETES-MELLITUS-
dc.subject.keywordPlusINCRETIN MIMETICS-
dc.subject.keywordPlusGLP-1 RECEPTOR-
dc.subject.keywordPlusEXTRACELLULAR DOMAIN-
dc.subject.keywordPlusCONJUGATED EXENDIN-4-
dc.subject.keywordPlusEXTENDED-RELEASE-
dc.subject.keywordPlusIV INHIBITORS-
dc.subject.keywordPlusIN-VIVO-
dc.subject.keywordPlusALBUMIN-
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