期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 15, 页码 4552-4557出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1420380112
关键词
alpha/beta-peptides; foldamers; protein-protein interactions; inhibitors; molecular recognition
资金
- NIH [GM056414, HL093282]
- University of Wisconsin-Madison Nanoscale Science and Engineering Center [DMR-0832760]
- Biotechnology Training Grant (NIH Grant) [T32 GM008349]
- Hilldale Undergraduate Research Fellowship from University of Wisconsin-Madison
- US DOE [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
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 alpha- and beta-amino acid residues (alpha/beta-peptides) that mimic several peptides derived from the three-helix bundle Z-domainscaffold. We show that alpha/beta-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 alpha/beta-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 alpha/beta-peptides that bind to two other protein partners, IgG and tumor necrosis factor-alpha. Because wellestablished selection techniques can identify high-affinity Z-domain derivatives from large DNA-encoded libraries, our findings should enable the design of biostable alpha/beta-peptides that bind tightly and specifically to diverse targets of biomedical interest. Such reagents would be useful for diagnostic and therapeutic applications.
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