Abstract
Glucagon-like peptide-1 (GLP-1) is a natural agonist for GLP-1R, a G protein-coupled receptor (GPCR) on the surface of pancreatic β cells. GLP-1R agoinsts are attractive for treatment of type 2 diabetes, but GLP-1 itself is rapidly degraded by peptidases in vivo. We describe a design strategy for retaining GLP-1-like activity while engendering prolonged activity in vivo, based on strategic replacement of native α residues with conformationally constrained β-amino acid residues. This backbone-modification approach may be useful for developing stabilized analogues of other peptide hormones.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Cells, Cultured
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Diabetes Mellitus, Type 2 / drug therapy
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Glucagon-Like Peptide 1 / analogs & derivatives*
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Glucagon-Like Peptide 1 / chemistry
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Glucagon-Like Peptide 1 / metabolism
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Glucagon-Like Peptide 1 / pharmacology*
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Glucagon-Like Peptide-1 Receptor
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Humans
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Mice
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Molecular Sequence Data
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Protein Stability
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Receptors, Glucagon / agonists*
Substances
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GLP1R protein, human
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Glp1r protein, mouse
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Glucagon-Like Peptide-1 Receptor
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Receptors, Glucagon
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Glucagon-Like Peptide 1