Targeting diverse protein?protein interaction interfaces with ?/?-peptides derived from the Z-domain scaffold [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 612.6 Reproduction, development, maturation
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2015
• Mô tả vật lý: Size: p. 4552-4557 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261195
• Chủ đề: 1. ??-peptides; 2. 59 basic biological sciences; 3. 60 applied life sciences; 4. Foldamers; 5. Inhibitors; 6. Molecular recognition; 7. Protein?protein interactions

Tóm tắt

 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 ?- and ?-amino acid residues (??/?-peptides?) that mimic several peptides derived from the three-helix bundle ?Z-domain? scaffold. We show that ?/?-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 ?/?-peptide inhibits the VEGF<
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 165<
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 -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 ?/?-peptides that bind to two other protein partners, IgG and tumor necrosis factor-?. 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 ?/?-peptides that bind tightly and specifically to diverse targets of biomedical interest. Finally, such reagents would be useful for diagnostic and therapeutic applications.