The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity

Máire E. Doyle, Michael J. Theodorakis, Harold W. Holloway, Michel Bernier, Nigel H. Greig, Josephine M. Egan

Research output: Contribution to journalArticle

Abstract

Exendin-4, a 39-amino acid (AA) peptide, is a long-acting agonist at the glucagon-like peptide-1 (GLP-1) receptor. Consequently, it may be preferable to GLP-1 as a long-term treatment for type 2 diabetes mellitus. Exendin-4 (Ex-4), unlike GLP-1, is not degraded by dipeptidyl peptidase IV (DPP IV), is less susceptible to degradation by neutral endopeptidase, and possesses a nine-AA C-terminal sequence absent from GLP-1. Here we examine the importance of these nine AAs for biological activity of Ex-4, a sequence of truncated Ex-4 analogs, and native GLP-1 and GLP-1 analogs to which all or parts of the C-terminal sequence have been added. We found that removing these AAs from Ex-4 to produce Ex (1-30) reduced the affinity for the GLP-1 receptor (GLP-1R) relative to Ex-4 (IC50: Ex-4, 3.22±0.9 nM; Ex (1-30), 32±5.8 nM) but made it comparable to that of GLP-1 (IC50: 44.9±3.2 nM). The addition of this nine-AA sequence to GLP-1 improved the affinity of both GLP-1 and the DPP IV resistant analog GLP-1 8-glycine for the GLP-1 receptor (IC50: GLP-1 Gly8 [GG], 220±23 nM; GLP-1 Gly8 Ex (31-39), 74±11 nM). Observations of the cAMP response in an insulinoma cell line show a similar trend for biological activity.

Original languageEnglish (US)
Pages (from-to)153-158
Number of pages6
JournalRegulatory Peptides
Volume114
Issue number2-3
DOIs
StatePublished - Jul 15 2003
Externally publishedYes

Keywords

  • Insulinotropic compounds
  • Peptide structure/function

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Clinical Biochemistry
  • Cellular and Molecular Neuroscience

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