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

Jung Gi Lee, Jae Ha Ryu, Seon Myung Kim, Moon Young Park, San Ho Kim, Young G. Shin, Jong Woo Sohn, Ha Hyung Kim, Zee Yong Park, Jae Young Seong, Jae Il Kim

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8 Citations (Scopus)

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 Ser33 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.

Original languageEnglish
Pages (from-to)59-68
Number of pages10
JournalBiochemical Pharmacology
Volume151
DOIs
Publication statusPublished - 2018 May 1

Keywords

  • Diabetes
  • Exendin-4
  • Fatty acid
  • GLP-1 receptor
  • Neutral endopeptidase 24.11

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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  • Cite this

    Lee, J. G., Ryu, J. H., Kim, S. M., Park, M. Y., Kim, S. H., Shin, Y. G., Sohn, J. W., Kim, H. H., Park, Z. Y., Seong, J. Y., & Kim, J. I. (2018). Replacement of the C-terminal Trp-cage of exendin-4 with a fatty acid improves therapeutic utility. Biochemical Pharmacology, 151, 59-68. https://doi.org/10.1016/j.bcp.2018.03.004