A Potent α/β-Peptide Analogue of GLP-1 with Prolonged Action in Vivo

Johnson, Lisa M.; Barrick, Stacey; Hager, Marlies V.; McFedries, Amanda; Homan, Edwin A.; Rabaglia, Mary E.; Keller, Mark P.; Attie, Alan D.; Saghatelian, Alan; Bisello, Alessandro; Gellman, Samuel H.

doi:10.1021/ja507168t

Cited by 84 publications

(108 citation statements)

References 45 publications

(53 reference statements)

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“…Indeed, α/β-VEGF-1 showed substantially greater resistance to proteinase K than the 59-mer α-peptide Z-VEGF. These observations are consistent with previous findings, involving other α-vs. α/β-peptide comparisons, that have shown that α→β replacements at multiple sites can substantially enhance polypeptide resistance to protease action (6)(7)(8)(9)35). Introduction of one additional Aib residue, to convert α/β-VEGF-1 into α/β-VEGF-2, conferred additional resistance to proteinase K (half-life, 670 min; >400-fold increase relative to Z-VEGF and >3,300-fold increase relative to α-VEGF-2).…”

Section: S-s S-s S-smentioning

confidence: 99%

“…The unnatural backbone diminishes α/β-peptide susceptibility to proteolytic degradation relative to conventional peptides (α-residues only, "α-peptides"). As a result, α/β-peptides can exhibit improved pharmacokinetic properties in vivo relative to analogous α-peptides (8,9). To date, however, the α/β-peptide strategy has been restricted to mimicry of isolated α-helices, which is a significant limitation given that most protein-protein interactions are mediated by surfaces that are broader than can be covered by a single, regular helix (1-4, 10).…”

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confidence: 99%

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Targeting diverse protein–protein interaction interfaces with α/β-peptides derived from the Z-domain scaffold

Checco

Kreitler

Thomas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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137

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Peptide-based agents derived from well-defined scaffolds offer an alternative to antibodies for selective and high-affinity recognition of large and topologically complex protein surfaces. Here, we describe a strategy for designing oligomers containing both α-and β-amino acid residues ("α/β-peptides") that mimic several peptides derived from the three-helix bundle "Z-domain" scaffold. We show that α/β-peptides derived from a Z-domain peptide targeting vascular endothelial growth factor (VEGF) can structurally and functionally mimic the binding surface of the parent peptide while exhibiting significantly decreased susceptibility to proteolysis. The tightest VEGF-binding α/β-peptide inhibits the VEGF 165 -induced proliferation of human umbilical vein endothelial cells. We demonstrate the versatility of this strategy by showing how principles underlying VEGF signaling inhibitors can be rapidly extended to produce Z-domain-mimetic α/β-peptides that bind to two other protein partners, IgG and tumor necrosis factor-α. Because wellestablished selection techniques can identify high-affinity Z-domain derivatives from large DNA-encoded libraries, our findings should enable the design of biostable α/β-peptides that bind tightly and specifically to diverse targets of biomedical interest. Such reagents would be useful for diagnostic and therapeutic applications.α/β-peptides | foldamers | protein-protein interactions | inhibitors | molecular recognition D esigned molecules that bind selectively to specific sites on proteins may serve as inhibitors of medically important macromolecular interactions or diagnostic tools for biomarker detection. Small molecules often fail for these applications because of the relatively large and irregularly shaped target surfaces (1-3). In contrast, large polypeptides (e.g., antibodies) can frequently be developed to recognize a protein surface with high affinity and selectivity and represent the state of the art for engineering ligands for specific biomacromolecular targets. Large polypeptides, however, suffer several disadvantages for in vivo applications, including costly production, low storage stability, and/ or low bioavailability because of rapid proteolytic degradation (4, 5).Backbone-modified peptides, an underexplored class of molecules, are proving to be a fruitful source of tight-binding and specific protein ligands. Peptidic oligomers that contain β-amino acid residues interspersed among α-residues ("α/β-peptides") can effectively mimic the recognition surface projected by an α-helix and thereby disrupt or augment protein-protein interactions in which one partner contributes a single helix to the interface (6, 7). The unnatural backbone diminishes α/β-peptide susceptibility to proteolytic degradation relative to conventional peptides (α-residues only, "α-peptides"). As a result, α/β-peptides can exhibit improved pharmacokinetic properties in vivo relative to analogous α-peptides (8, 9). To date, however, the α/β-peptide strategy has been restricted to mimicry of isolated α-helices, ...

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Section: S-s S-s S-smentioning

confidence: 99%

mentioning

confidence: 99%

Targeting diverse protein–protein interaction interfaces with α/β-peptides derived from the Z-domain scaffold

Checco

Kreitler

Thomas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

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“…In this study, a hexameric β-peptide 14-helix was utilized with a surface engineered to bind to Aβ aggregates. Two-stage binding was observed in the solution phase when the foldameric recognition segments were attached to a tetravalent oligo-lysine dendron template (8). The first stage has a low nanomolar affinity toward Aβ oligomers with fractional stoichiometry indicating that multiple copies of aggregated Aβ chains are necessary to form a surface patch to be recognized by the tetravalent ligand.…”

Section: Discussionmentioning

confidence: 99%

“…Somatostatin receptor [7] GLP-1 receptor, [8] PTHR1, [9] the p53-hDM2, [10] the BH3-Bcl-x L [11,12] and the VEGF-VEGFR1 [13] interactions, the gp41 virus cell infusion protein assembly [14], the γ-secretase enzyme [15] and amyloid aggregation. [16] Whilst biomimetic molecular recognition can be achieved with foldamers, their application in therapy, diagnostics and as analytical tools is still a major challenge.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

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Multivalent foldamer-based affinity assay for selective recognition of Aβ oligomers

Olajos

Bartus

Schuster

et al. 2017

Analytica Chimica Acta

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Mimicking the molecular recognition functionality of antibodies is a great challenge. Foldamers are attractive candidates because of their relatively small size and designable interaction surface. This paper describes a sandwich type enzyme-linked immunoassay with a tetravalent β-peptide foldamer helix array as capture element and enzyme labeled tracer antibodies. The assay was found to be selective to β-amyloid oligomeric species with surface features transiently present in ongoing aggregation. In optimized conditions, with special emphasis on the foldamer immobilization, a detection limit of 5 pM was achieved with a linear range of 10 -500 pM. These results suggest that protein mimetic foldamers can be useful tools in biosensors and affinity assays.

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Cyclized Helical Peptides

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A Potent α/β-Peptide Analogue of GLP-1 with Prolonged Action in Vivo

Cited by 84 publications

References 45 publications

Targeting diverse protein–protein interaction interfaces with α/β-peptides derived from the Z-domain scaffold

Targeting diverse protein–protein interaction interfaces with α/β-peptides derived from the Z-domain scaffold

Multivalent foldamer-based affinity assay for selective recognition of Aβ oligomers

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