Iterative non-proteinogenic residue incorporation yields α/β-peptides with a helix-loop-helix tertiary structure and high affinity for VEGF

Authors

James W. Checco, University of Nebraska-LincolnFollow
Samuel H. Gellman, University of Wisconsin-Madison

Date of this Version

2-1-2017

Citation

Chembiochem. 2017 February 01; 18(3): 291–299. doi:10.1002/cbic.201600545.

Comments

Chembiochem. Author manuscript; available in PMC 2018 February 01.

Abstract

Inhibition of specific protein-protein interactions is attractive for a range of therapeutic applications, but the large and irregularly shaped contact surfaces involved in many such interactions make it challenging to design synthetic antagonists. Here, we describe the development of backbone-modified peptides containing both α- and β-amino acid residues (“α/β-peptides”) that target the receptor-binding surface of vascular endothelial growth factor (VEGF). Our approach is based on the Z-domain, which adopts a three-helix bundle tertiary structure. We show how a two-helix “mini-Z-domain” can be modified to contain β and other non-proteinogenic residues while retaining the target-binding epitope using iterative non-natural residue incorporation. The resulting α/β-peptides are less susceptible to proteolysis than is their parent α-peptide, and some of these α/β-peptides match the full-length Z-domain in terms of affinity for receptor-recognition surfaces on the VEGF homodimer.