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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CHO Cells
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Circular Dichroism
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Cricetulus
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Cyclic AMP / biosynthesis
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Glucagon-Like Peptide-1 Receptor
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Humans
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Hydrophobic and Hydrophilic Interactions
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Models, Molecular
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Nuclear Magnetic Resonance, Biomolecular
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Peptides, Cyclic / chemistry*
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Peptides, Cyclic / pharmacology
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Protein Structure, Secondary
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Radioligand Assay
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Receptors, Glucagon / agonists*
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Structure-Activity Relationship
Substances
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GLP1R protein, human
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Glucagon-Like Peptide-1 Receptor
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Peptides, Cyclic
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Receptors, Glucagon
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Cyclic AMP