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

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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
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Issue Date
2018-05
Language
English
Article Type
Article
Keywords

GLUCAGON-LIKE PEPTIDE-1; TYPE-2 DIABETES-MELLITUS; INCRETIN MIMETICS; GLP-1 RECEPTOR; EXTRACELLULAR DOMAIN; CONJUGATED EXENDIN-4; EXTENDED-RELEASE; IV INHIBITORS; IN-VIVO; ALBUMIN

Citation

BIOCHEMICAL PHARMACOLOGY, v.151, pp.59 - 68

ISSN
0006-2952
DOI
10.1016/j.bcp.2018.03.004
URI
http://hdl.handle.net/10203/241084
Appears in Collection
BS-Journal Papers(저널논문)
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