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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [1];  [1];  [1];  [2];  [1];  [3];  [4];  [1]
  1. Univ. of Wisconsin, Madison, WI (United States). Dept. of Chemistry
  2. Univ. of Wisconsin, Madison, WI (United States). Dept. of Biomedical Engineering
  3. Univ. of Wisconsin, Madison, WI (United States). Dept. of Biomedical Engineering. Dept. of Orthopedics and Rehabilitation
  4. Univ. of Wisconsin, Madison, WI (United States). Dept. of Bacteriology
+ Show Author Affiliations

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. In this paper, 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. Finally, such reagents would be useful for diagnostic and therapeutic applications.

Research Organization:
Univ. of Wisconsin, Madison, WI (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); National Science Foundation (NSF); Michigan Economic Development Corporation (United States); Michigan Technology Tri-Corridor (United States)
Grant/Contract Number:
AC02-06CH11357; GM056414; HL093282; T32 GM008349; DMR-0832760; 085P1000817
OSTI ID:
1182327
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, Issue 15; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 79 works
Citation information provided by
Web of Science

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Cited By (17)

An α-Helix-Mimicking 12,13-Helix: Designed α/β/γ-Foldamers as Selective Inhibitors of Protein-Protein Interactions journal July 2016
Iterative Nonproteinogenic Residue Incorporation Yields α/β-Peptides with a Helix-Loop-Helix Tertiary Structure and High Affinity for VEGF journal January 2017
Exploring the Functional Consequences of Protein Backbone Alteration in Ubiquitin through Native Chemical Ligation journal July 2019
Anion Recognition by Aliphatic Helical Oligoureas journal August 2016
De Novo Modular Development of a Foldameric Protein-Protein Interaction Inhibitor for Separate Hot Spots: A Dynamic Covalent Assembly Approach journal March 2017
Lithium hexamethyldisilazide initiated superfast ring opening polymerization of alpha-amino acid N-carboxyanhydrides journal December 2018
Enantiomeric glycosylated cationic block co-beta-peptides eradicate Staphylococcus aureus biofilms and antibiotic-tolerant persisters journal October 2019
Proteomimetics as protein-inspired scaffolds with defined tertiary folding patterns journal February 2020
Self-assembled vesicles of urea-tethered foldamers as hydrophobic drug carriers journal January 2016
Surfactant-facilitated crystallisation of water-soluble foldamers journal January 2016
Crystal structure of a protein–aromatic foldamer composite: macromolecular chiral resolution journal January 2019
High-resolution structures of a heterochiral coiled coil journal October 2015
Applications of in Silico Methods for Design and Development of Drugs Targeting Protein-Protein Interactions journal May 2019
Recognition of Class II MHC Peptide Ligands That Contain β-Amino Acids journal August 2019
An α-Helix-Mimicking 12,13-Helix: Designed α/β/γ-Foldamers as Selective Inhibitors of Protein-Protein Interactions journal July 2016
Anion Recognition by Aliphatic Helical Oligoureas journal October 2016
Novel Materials From the Supramolecular Self-Assembly of Short Helical β3-Peptide Foldamers journal February 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
α/β-peptides
foldamers
protein–protein interactions
inhibitors
molecular recognition