Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening

Cassandra Koole, Denise Wootten, John Simms, Celine Valant, Rohan Sridhar, Owen L Woodman, Laurence J Miller, Roger J Summers, Arthur Christopoulos, Patrick M Sexton

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex, with multiple endogenous peptides that can interact with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can each exist in an amidated form and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound 2 (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline) and quercetin, and their ability to modify binding and signaling (cAMP formation, intracellular Ca(2+) mobilization, and extracellular signal-regulated kinase 1/2 phosphorylation) of each of the naturally occurring endogenous peptide agonists, as well as the clinically used peptide mimetic exendin-4. We identified and quantified stimulus bias across multiple endogenous peptides, with response profiles for truncated GLP-1 peptides distinct from those of either the full-length GLP-1 peptides or oxyntomodulin, the first demonstration of such behavior at the GLP-1 receptor. Compound 2 selectively augmented cAMP signaling but did so in a peptide-agonist dependent manner having greatest effect on oxyntomodulin, weaker effect on truncated GLP-1 peptides, and negligible effect on other peptide responses; these effects were principally driven by parallel changes in peptide agonist affinity. In contrast, quercetin selectively modulated calcium signaling but with effects only on truncated GLP-1 peptides or exendin and not oxyntomodulin or full-length peptides. These data have significant implications for how GLP-1 receptor targeted drugs are screened and developed, whereas the allosterically driven, agonist-selective, stimulus bias highlights the potential for distinct clinical efficacy depending on the properties of individual drugs.

Original languageEnglish
Pages (from-to)456-465
Number of pages10
JournalMolecular Pharmacology
Volume78
Issue number3
DOIs
Publication statusPublished - Sep 2010

Fingerprint

Preclinical Drug Evaluations
Ligands
Peptides
Oxyntomodulin
Glucagon-Like Peptide 1
Quercetin
Glucagon-Like Peptide-1 Receptor
Calcium Signaling
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Pharmaceutical Preparations

Keywords

  • Animals
  • Cricetinae
  • Drug Evaluation, Preclinical
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Ligands
  • Mitogen-Activated Protein Kinase 3
  • Oxyntomodulin
  • Peptides
  • Receptors, Glucagon
  • Signal Transduction
  • Venoms
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner : implications for drug screening. / Koole, Cassandra; Wootten, Denise; Simms, John; Valant, Celine; Sridhar, Rohan; Woodman, Owen L; Miller, Laurence J; Summers, Roger J; Christopoulos, Arthur; Sexton, Patrick M.

In: Molecular Pharmacology, Vol. 78, No. 3, 09.2010, p. 456-465.

Research output: Contribution to journalArticle

Koole, Cassandra ; Wootten, Denise ; Simms, John ; Valant, Celine ; Sridhar, Rohan ; Woodman, Owen L ; Miller, Laurence J ; Summers, Roger J ; Christopoulos, Arthur ; Sexton, Patrick M. / Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner : implications for drug screening. In: Molecular Pharmacology. 2010 ; Vol. 78, No. 3. pp. 456-465.
@article{9d1f704ffdf34277b8287712012a0af0,
title = "Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening",
abstract = "The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex, with multiple endogenous peptides that can interact with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can each exist in an amidated form and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound 2 (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline) and quercetin, and their ability to modify binding and signaling (cAMP formation, intracellular Ca(2+) mobilization, and extracellular signal-regulated kinase 1/2 phosphorylation) of each of the naturally occurring endogenous peptide agonists, as well as the clinically used peptide mimetic exendin-4. We identified and quantified stimulus bias across multiple endogenous peptides, with response profiles for truncated GLP-1 peptides distinct from those of either the full-length GLP-1 peptides or oxyntomodulin, the first demonstration of such behavior at the GLP-1 receptor. Compound 2 selectively augmented cAMP signaling but did so in a peptide-agonist dependent manner having greatest effect on oxyntomodulin, weaker effect on truncated GLP-1 peptides, and negligible effect on other peptide responses; these effects were principally driven by parallel changes in peptide agonist affinity. In contrast, quercetin selectively modulated calcium signaling but with effects only on truncated GLP-1 peptides or exendin and not oxyntomodulin or full-length peptides. These data have significant implications for how GLP-1 receptor targeted drugs are screened and developed, whereas the allosterically driven, agonist-selective, stimulus bias highlights the potential for distinct clinical efficacy depending on the properties of individual drugs.",
keywords = "Animals, Cricetinae, Drug Evaluation, Preclinical, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Insulin, Ligands, Mitogen-Activated Protein Kinase 3, Oxyntomodulin, Peptides, Receptors, Glucagon, Signal Transduction, Venoms, Journal Article, Research Support, Non-U.S. Gov't",
author = "Cassandra Koole and Denise Wootten and John Simms and Celine Valant and Rohan Sridhar and Woodman, {Owen L} and Miller, {Laurence J} and Summers, {Roger J} and Arthur Christopoulos and Sexton, {Patrick M}",
year = "2010",
month = "9",
doi = "10.1124/mol.110.065664",
language = "English",
volume = "78",
pages = "456--465",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner

T2 - implications for drug screening

AU - Koole, Cassandra

AU - Wootten, Denise

AU - Simms, John

AU - Valant, Celine

AU - Sridhar, Rohan

AU - Woodman, Owen L

AU - Miller, Laurence J

AU - Summers, Roger J

AU - Christopoulos, Arthur

AU - Sexton, Patrick M

PY - 2010/9

Y1 - 2010/9

N2 - The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex, with multiple endogenous peptides that can interact with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can each exist in an amidated form and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound 2 (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline) and quercetin, and their ability to modify binding and signaling (cAMP formation, intracellular Ca(2+) mobilization, and extracellular signal-regulated kinase 1/2 phosphorylation) of each of the naturally occurring endogenous peptide agonists, as well as the clinically used peptide mimetic exendin-4. We identified and quantified stimulus bias across multiple endogenous peptides, with response profiles for truncated GLP-1 peptides distinct from those of either the full-length GLP-1 peptides or oxyntomodulin, the first demonstration of such behavior at the GLP-1 receptor. Compound 2 selectively augmented cAMP signaling but did so in a peptide-agonist dependent manner having greatest effect on oxyntomodulin, weaker effect on truncated GLP-1 peptides, and negligible effect on other peptide responses; these effects were principally driven by parallel changes in peptide agonist affinity. In contrast, quercetin selectively modulated calcium signaling but with effects only on truncated GLP-1 peptides or exendin and not oxyntomodulin or full-length peptides. These data have significant implications for how GLP-1 receptor targeted drugs are screened and developed, whereas the allosterically driven, agonist-selective, stimulus bias highlights the potential for distinct clinical efficacy depending on the properties of individual drugs.

AB - The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex, with multiple endogenous peptides that can interact with the receptor, including full-length (1-37) and truncated (7-37) forms of GLP-1 that can each exist in an amidated form and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound 2 (6,7-dichloro2-methylsulfonyl-3-tert-butylaminoquinoxaline) and quercetin, and their ability to modify binding and signaling (cAMP formation, intracellular Ca(2+) mobilization, and extracellular signal-regulated kinase 1/2 phosphorylation) of each of the naturally occurring endogenous peptide agonists, as well as the clinically used peptide mimetic exendin-4. We identified and quantified stimulus bias across multiple endogenous peptides, with response profiles for truncated GLP-1 peptides distinct from those of either the full-length GLP-1 peptides or oxyntomodulin, the first demonstration of such behavior at the GLP-1 receptor. Compound 2 selectively augmented cAMP signaling but did so in a peptide-agonist dependent manner having greatest effect on oxyntomodulin, weaker effect on truncated GLP-1 peptides, and negligible effect on other peptide responses; these effects were principally driven by parallel changes in peptide agonist affinity. In contrast, quercetin selectively modulated calcium signaling but with effects only on truncated GLP-1 peptides or exendin and not oxyntomodulin or full-length peptides. These data have significant implications for how GLP-1 receptor targeted drugs are screened and developed, whereas the allosterically driven, agonist-selective, stimulus bias highlights the potential for distinct clinical efficacy depending on the properties of individual drugs.

KW - Animals

KW - Cricetinae

KW - Drug Evaluation, Preclinical

KW - Glucagon-Like Peptide 1

KW - Glucagon-Like Peptide-1 Receptor

KW - Insulin

KW - Ligands

KW - Mitogen-Activated Protein Kinase 3

KW - Oxyntomodulin

KW - Peptides

KW - Receptors, Glucagon

KW - Signal Transduction

KW - Venoms

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1124/mol.110.065664

DO - 10.1124/mol.110.065664

M3 - Article

VL - 78

SP - 456

EP - 465

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 3

ER -