UNIT 18.8 Overview of Solid Phase Synthesis of “Difficult Peptide” Sequences

  1. Anna K. Tickler,
  2. John D. Wade

Published Online: 1 NOV 2007

DOI: 10.1002/0471140864.ps1808s50

Current Protocols in Protein Science

Current Protocols in Protein Science

How to Cite

Tickler, A. K. and Wade, J. D. 2007. Overview of Solid Phase Synthesis of “Difficult Peptide” Sequences. Current Protocols in Protein Science. 50:18.8:18.8.1–18.8.6.

Author Information

  1. University of Melbourne, Victoria, Australia

Publication History

  1. Published Online: 1 NOV 2007
  2. Published Print: NOV 2007


Solid-phase peptide synthesis has contributed immeasurably to the understanding of the chemistry and biology of peptides by enabling their ready preparation in small quantities up to the ton scale. The advantages of the technology, including its simplicity, ease of operation, and general efficiency have far outweighed its limitations. However, despite the general effectiveness of the solid phase synthesis methodology, some peptides are resistant to efficient assembly and are known as “difficult peptides.” Such sequences can present serious challenges to the peptide researcher and have been the subject of considerable investigation. This phenomenon is described together with modern approaches designed to minimize or overcome this hitherto long-standing and vexing problem. Curr. Protoc. Protein Sci. 50:18.8.1-18.8.6. © 2007 by John Wiley & Sons, Inc.


  • amino acid derivatives;
  • “difficult peptide” sequences;
  • secondary structure;
  • solid phase peptide synthesis