skip to main content

SciTech ConnectSciTech Connect

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

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.
Authors:
 [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
Publication Date:
OSTI Identifier:
1182327
Grant/Contract Number:
AC02-06CH11357; GM056414; HL093282; T32 GM008349; DMR-0832760; 085P1000817
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 112; Journal Issue: 15; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Univ. of Wisconsin, Madison, WI (United States)
Sponsoring Org:
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)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; α/β-peptides; foldamers; protein–protein interactions; inhibitors; molecular recognition