title: Short Hydrophobic Peptides with Cyclic Constraints Are Potent Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists.
abstract: Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonists at nM concentrations in a cAMP assay. 2D NMR and CD spectra revealed an N-terminal β-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small molecule agonists of the GLP-1 receptor to treat type 2 diabetes.
authors.affiliation: †Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Huy N
authors.initials: HN
authors.lastname: Hoang
authors.forename: Kun
authors.initials: K
authors.lastname: Song
authors.affiliation: †Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hill
authors.forename: David R
authors.initials: DR
authors.lastname: Derksen
authors.forename: David J
authors.initials: DJ
authors.lastname: Edmonds
authors.affiliation: †Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: W Mei
authors.initials: WM
authors.lastname: Kok
authors.forename: Chris
authors.initials: C
authors.lastname: Limberakis
authors.forename: Spiros
authors.initials: S
authors.lastname: Liras
authors.forename: Paula M
authors.initials: PM
authors.lastname: Loria
authors.forename: Vincent
authors.initials: V
authors.lastname: Mascitti
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.affiliation: †Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Mitchell
authors.forename: David W
authors.initials: DW
authors.lastname: Piotrowski
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Robert V
authors.initials: RV
authors.lastname: Stanton
authors.affiliation: †Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jacky Y
authors.initials: JY
authors.lastname: Suen
authors.forename: Jane M
authors.initials: JM
authors.lastname: Withka
authors.forename: David A
authors.initials: DA
authors.lastname: Griffith
authors.affiliation: †Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000818:Animals; D016466:CHO Cells; D002942:Circular Dichroism; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D018027:Receptors, Glucagon / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D010456:Peptides, Cyclic; D018027:Receptors, Glucagon; D000242:Cyclic AMP