Synthesis of hydrogen-bond surrogate α-helices as inhibitors of protein-protein interactions

Stephen E. Miller, Paul F. Thomson, Paramjit S. Arora

Research output: Contribution to journalArticlepeer-review


The α-helix is a prevalent secondary structure in proteins and is critical in mediating protein-protein interactions (PPIs). Peptide mimetics that adopt stable helices have become powerful tools for the modulation of PPIs in vitro and in vivo. Hydrogen-bond surrogate (HBS) α-helices utilize a covalent bond in place of an N-terminal i to i+4 hydrogen bond and have been used to target and disrupt PPIs that become dysregulated in disease states. These compounds have improved conformational stability and cellular uptake as compared to their linear peptide counterparts. The protocol presented here describes current methodology for the synthesis of HBS α-helical mimetics. The solid-phase synthesis of HBS helices involves solid-phase peptide synthesis with three key steps involving incorporation of N-allyl functionality within the backbone of the peptide, coupling of a secondary amine, and a ring-closing metathesis step.

Original languageEnglish (US)
Pages (from-to)101-116
Number of pages16
JournalCurrent protocols in chemical biology
Issue number2
StatePublished - Jun 2014


  • hydrogen-bond surrogate
  • protein-protein interactions
  • α-helix mimetics

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology


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