A β-Peptide Agonist of the GLP-1 Receptor, a Class B GPCR

Denton, Elizabeth V.; Craig, Cody J.; Pongratz, Rebecca L.; Appelbaum, Jacob; Doerner, Amy; Narayanan, Arjun; Shulman, Gerald I.; Cline, Gary W.; Schepartz, Alanna

doi:10.1021/ol402568j

Cited by 40 publications

(46 citation statements)

References 50 publications

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“…Introduction of just one or two α➔β replacements in the central portion of a PTHR1 agonist peptide can substantially diminish receptor activation potency, 28–30 which shows that proper selection of substitution sites in peptide hormone mimics is crucial. 30 In a study of 19-mer peptides that adopt a specific but irregular conformation and bind to vascular endothelial growth factor (VEGF), we found that it was not possible to introduce α➔β replacements without diminution of affinity for VEGF. 31 Therefore, whether α/β segments can serve as functional mimics of non-helical or conformationally uncharacterized α-peptide segments remains an open question.…”

Section: Introductionmentioning

confidence: 99%

Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad β Residue Distribution

et al. 2017

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The parathyroid hormone receptor-1 (PTHR1) is a member of the B-family of GPCRs; these receptors are activated by long polypeptide hormones and constitute targets of drug development efforts. Parathyroid hormone (PTH; 84 residues) and PTH-related protein (PTHrP; 141 residues) are natural agonists of PTHR1, and an N-terminal fragment of PTH, PTH(1−34), is used clinically to treat osteoporosis. Conventional peptides in the 20-40-mer length range are rapidly degraded by proteases, which may limit their biomedical utility. We have used the PTHR1-ligand system to explore the impact of broadly distributed replacement of α-amino acid residues with β-amino acid residues on susceptibility to proteolysis and agonist activity. This effort led us to identify new PTHR1 agonists that contain α→β replacements throughout their sequences, manifest potent agonist activity in cellular assays, and display remarkable resistance to proteolysis. The strategy we have employed suggests a path toward identifying protease-resistant agonists of other B-family GPCRs.

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Section: Introductionmentioning

confidence: 99%

Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad β Residue Distribution

et al. 2017

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“…In previous studies, PTH analogs containing one to three β-residue replacements were used to probe local conformational requirements, and many of these replacements caused profound declines in agonist activity 9,10 . The peptide hormone GLP-1(7-37), which activates a different B-family G protein–coupled receptor, parallels PTH(1-34) in that the C-terminal portion is α-helical when bound to the receptor 11 ; recent efforts to replace the α-helix with a purely β-residue segment essentially abolished activity 12 . In contrast, we show that proper choice of β-residue identity and location allows α→β residue replacement at up to seven distributed sites with maintenance of PTH(1-34)-like potency, but alteration of the pharmacokinetic profile.…”

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confidence: 99%

“…14). Alternative strategies for introducing α→β replacements in peptide hormones have been largely unsuccessful in terms of retaining native potency 9,10,12 . α/β-peptides A5-D5 were easily prepared by conventional solid-phase synthesis.…”

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confidence: 99%

Backbone modification of a polypeptide drug alters duration of action in vivo

et al. 2014

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Systematic modification of the backbone of bioactive polypeptides through β-amino acid residue incorporation could provide a strategy for generating molecules with improved drug properties, but such alterations can result in lower receptor affinity and potency. Using an agonist of parathyroid hormone receptor-1 (PTHR1), a G protein–coupled receptor in the B-family, we present an approach for α→β residue replacement that enables both high activity and improved pharmacokinetic properties in vivo.

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“…A long α-helix formed in the C-terminal portion of exenatide makes extensive contacts with the extracellular domain of GLP-1R [47]. Replacement of this α-helix-forming segment with a β-peptide segment caused a dramatic loss in agonist potency [48]. …”

Section: β-Peptidesmentioning

confidence: 99%

Targeting recognition surfaces on natural proteins with peptidic foldamers

Checco

Gellman

2016

Current Opinion in Structural Biology

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Molecules intended to antagonize protein–protein interactions or augment polypeptide-based signaling must bind tightly to large and specific surfaces on target proteins. Some types of unnatural oligomers with discrete folding propensities (‘foldamers’) have recently been shown to display this capability. This review covers important recent advances among several classes of foldamers, including α-peptides with secondary structures stabilized by covalent bonds, d-α-peptides, α/β-peptides and oligo-oxopiperazines. Recent advances in this area have involved enhancing membrane permeability to provide access to intracellular protein targets, improving pharmacokinetics and duration of action in vivo, and developing strategies appropriate for targeting large and irregularly-shaped protein surfaces.

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A β-Peptide Agonist of the GLP-1 Receptor, a Class B GPCR

Cited by 40 publications

References 50 publications

Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad β Residue Distribution

Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad β Residue Distribution

Backbone modification of a polypeptide drug alters duration of action in vivo

Targeting recognition surfaces on natural proteins with peptidic foldamers

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