title: Targeting diverse protein-protein interaction interfaces with α/β-peptides derived from the Z-domain scaffold.
abstract: 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 VEGF165-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 well-established 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.
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: James W
authors.initials: JW
authors.lastname: Checco
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Dale F
authors.initials: DF
authors.lastname: Kreitler
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Thomas
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705;
authors.forename: David G
authors.initials: DG
authors.lastname: Belair
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Rettko
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705; Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, WI 53705; and gellman@chem.wisc.edu wlmurphy@wisc.edu forest@bact.wisc.edu.
authors.forename: William L
authors.initials: WL
authors.lastname: Murphy
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706 gellman@chem.wisc.edu wlmurphy@wisc.edu forest@bact.wisc.edu.
authors.forename: Katrina T
authors.initials: KT
authors.lastname: Forest
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706; gellman@chem.wisc.edu wlmurphy@wisc.edu forest@bact.wisc.edu.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007074:Immunoglobulin G; D010455:Peptides; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: foldamers; inhibitors; molecular recognition; protein–protein interactions; α/β-peptides
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