Glucagon-like peptide-1 and its class B G protein-coupled receptors: A long march to therapeutic successes

Chris de Graaf, Dan Donnelly, Denise Wootten, Jesper Lau, Patrick M. Sexton, Laurence J Miller, Jung Mo Ahn, Jiayu Liao, Madeleine M. Fletcher, Dehua Yang, Alastair J H Brown, Caihong Zhou, Jiejie Deng, Ming Wei Wang

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Theglucagon-likepeptide (GLP)-1receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secretedfromthreemajor tissues inhumans,enteroendocrine L cells in the distal intestine, a cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including glucose homeostasis and regulation of gastric motility and food intake. Peptidic analogs of GLP-1 have been successfully developed with enhanced bioavailability and pharmacological activity. Physiologic and biochemical studies with truncated, chimeric, and mutated peptides and GLP-1R variants, together with ligand-bound crystal structures of the extracellular domain and the first three-dimensional structures of the 7-helical transmembrane domain of class B GPCRs, have provided the basis for a twodomain-binding mechanism of GLP-1 with its cognate receptor. Although efforts in discovering therapeutically viable nonpeptidicGLP-1R agonists have been hampered, small-moleculemodulators offer complementary chemical tools to peptide analogs to investigate ligand-directed biased cellular signaling of GLP-1R. The integrated pharmacological and structural information of different GLP-1 analogs and homologous receptors give new insights into the molecular determinants of GLP-1R ligand selectivity and functional activity, thereby providing novel opportunities in the design and development of more efficacious agents to treat metabolic disorders.

Original languageEnglish (US)
Pages (from-to)954-1013
Number of pages60
JournalPharmacological Reviews
Volume68
Issue number4
DOIs
StatePublished - Oct 1 2016

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Glucagon-Like Peptide 1
G-Protein-Coupled Receptors
Ligands
Enteroendocrine Cells
Pharmacology
Peptides
Peptide Hormones
Therapeutics
Type 2 Diabetes Mellitus
Biological Availability
Intestines
Pancreas
Stomach
Homeostasis
Central Nervous System
Obesity
Eating
Glucose

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Glucagon-like peptide-1 and its class B G protein-coupled receptors : A long march to therapeutic successes. / de Graaf, Chris; Donnelly, Dan; Wootten, Denise; Lau, Jesper; Sexton, Patrick M.; Miller, Laurence J; Ahn, Jung Mo; Liao, Jiayu; Fletcher, Madeleine M.; Yang, Dehua; Brown, Alastair J H; Zhou, Caihong; Deng, Jiejie; Wang, Ming Wei.

In: Pharmacological Reviews, Vol. 68, No. 4, 01.10.2016, p. 954-1013.

Research output: Contribution to journalArticle

de Graaf, C, Donnelly, D, Wootten, D, Lau, J, Sexton, PM, Miller, LJ, Ahn, JM, Liao, J, Fletcher, MM, Yang, D, Brown, AJH, Zhou, C, Deng, J & Wang, MW 2016, 'Glucagon-like peptide-1 and its class B G protein-coupled receptors: A long march to therapeutic successes', Pharmacological Reviews, vol. 68, no. 4, pp. 954-1013. https://doi.org/10.1124/pr.115.011395
de Graaf, Chris ; Donnelly, Dan ; Wootten, Denise ; Lau, Jesper ; Sexton, Patrick M. ; Miller, Laurence J ; Ahn, Jung Mo ; Liao, Jiayu ; Fletcher, Madeleine M. ; Yang, Dehua ; Brown, Alastair J H ; Zhou, Caihong ; Deng, Jiejie ; Wang, Ming Wei. / Glucagon-like peptide-1 and its class B G protein-coupled receptors : A long march to therapeutic successes. In: Pharmacological Reviews. 2016 ; Vol. 68, No. 4. pp. 954-1013.
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