Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist.
Administration, Oral
Aminopyridines
/ pharmacology
Animals
Anti-Obesity Agents
/ pharmacology
Benzamides
/ pharmacology
Cryoelectron Microscopy
Glucagon-Like Peptide-1 Receptor
/ agonists
HEK293 Cells
Humans
Hypoglycemic Agents
/ pharmacology
Incretins
/ pharmacology
Macaca fascicularis
Male
Mice
Mice, Transgenic
Models, Molecular
Mutagenesis, Site-Directed
Protein Domains
/ genetics
Rats
Species Specificity
Swine
Tryptophan
/ genetics
LY3502970
OWL833
cryoelectron microscopy
glucagon-like peptide-1 receptor
type 2 diabetes mellitus
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
24 11 2020
24 11 2020
Historique:
pubmed:
13
11
2020
medline:
20
1
2021
entrez:
12
11
2020
Statut:
ppublish
Résumé
Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein-coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.
Identifiants
pubmed: 33177239
pii: 2014879117
doi: 10.1073/pnas.2014879117
pmc: PMC7703558
doi:
Substances chimiques
Aminopyridines
0
Anti-Obesity Agents
0
Benzamides
0
GLP1R protein, human
0
Glp1r protein, mouse
0
Glucagon-Like Peptide-1 Receptor
0
Hypoglycemic Agents
0
Incretins
0
PF-06372222
0
Tryptophan
8DUH1N11BX
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
29959-29967Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: D.B.W., A.D.S., B.A.D., M.P.C., F.S.W., and K.W.S. may own Eli Lilly and Company stock. T.S.K. is cofounder and president of ConfometRx. B.K.K. is a cofounder of and consultant for ConfometRx.
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