Unit

Chemical Synthesis of Hydrocarbon-Stapled Peptides for Protein Interaction Research and Therapeutic Targeting

  1. Gregory H. Bird,
  2. W. Christian Crannell,
  3. Loren D. Walensky

Published Online: 1 SEP 2011

DOI: 10.1002/9780470559277.ch110042

Current Protocols in Chemical Biology

Current Protocols in Chemical Biology

How to Cite

Bird, G. H., Christian Crannell, W. and Walensky, L. D. 2011. Chemical Synthesis of Hydrocarbon-Stapled Peptides for Protein Interaction Research and Therapeutic Targeting. Current Protocols in Chemical Biology. 3:99–117.

Author Information

  1. Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts

Publication History

  1. Published Online: 1 SEP 2011
  2. Published Print: SEP 2011

Abstract

The peptide α-helix represents one of nature's most featured protein shapes and is employed in a diversity of protein architectures, from the cytoskeletal infrastructure to the most intimate contact points between crucial signaling proteins. By installing an all-hydrocarbon crosslink into native sequences, the shape and biological activity of natural peptide α-helices can be recapitulated, yielding a chemical toolbox that can be used both to interrogate the protein interactome and to modulate interaction networks for potential therapeutic benefit. Here, current methodology for synthesizing stabilized α-helices (SAH) corresponding to key protein interaction domains is described. A stepwise approach is taken for the production of crosslinking non-natural amino acids, incorporation of the residues into peptide templates, and application of ruthenium-catalyzed ring-closing metathesis to generate hydrocarbon-stapled peptides. Through facile derivatization and functionalization steps, SAHs can be tailored for a broad range of applications in biochemical, structural, proteomic, cellular, and in vivo studies. Curr. Protoc. Chem. Biol. 3:99-117 © 2011 by John Wiley & Sons, Inc.

Keywords:

  • α-helix;
  • peptide;
  • hydrocarbon stapling;
  • olefin metathesis;
  • photoreactive;
  • protein interaction;
  • targeting