Hydrogen Bond Surrogate Stabilization of β-Hairpins

ACS Chem Biol. 2018 Aug 17;13(8):2027-2032. doi: 10.1021/acschembio.8b00641. Epub 2018 Jul 18.

Abstract

Peptide secondary and tertiary structure motifs frequently serve as inspiration for the development of protein-protein interaction (PPI) inhibitors. While a wide variety of strategies have been used to stabilize or imitate α-helices, similar strategies for β-sheet stabilization are more limited. Synthetic scaffolds that stabilize reverse turns and cross-strand interactions have provided important insights into β-sheet stability and folding. However, these templates occupy regions of the β-sheet that might impact the β-sheet's ability to bind at a PPI interface. Here, we present the hydrogen bond surrogate (HBS) approach for stabilization of β-hairpin peptides. The HBS linkage replaces a cross-strand hydrogen bond with a covalent linkage, conferring significant conformational and proteolytic resistance. Importantly, this approach introduces the stabilizing linkage in the buried β-sheet interior, retains all side chains for further functionalization, and allows efficient solid-phase macrocyclization. We anticipate that HBS stabilization of PPI β-sheets will enhance the development of β-sheet PPI inhibitors and expand the repertoire of druggable PPIs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cyclization
  • Hydrogen Bonding
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Protein Conformation, beta-Strand
  • Protein Engineering / methods
  • Protein Stability

Substances

  • Peptides