Replacement of the C-terminal Trp-cage of exendin-4 with a fatty acid improves therapeutic utility
- Authors
- Lee, Jung Gi; Ryu, Jae Ha; Kim, Seon-Myung; Park, Moon-Young; Kim, San-Ho; Shin, Young G.; Sohn, Jong-Woo; Kim, Ha Hyung; Park, Zee-Yong; Seong, Jae Young; Kim, Jae Il
- Issue Date
- 5월-2018
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- Diabetes; Exendin-4; Fatty acid; GLP-1 receptor; Neutral endopeptidase 24.11
- Citation
- BIOCHEMICAL PHARMACOLOGY, v.151, pp.59 - 68
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOCHEMICAL PHARMACOLOGY
- Volume
- 151
- Start Page
- 59
- End Page
- 68
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/75607
- DOI
- 10.1016/j.bcp.2018.03.004
- ISSN
- 0006-2952
- 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.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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