Amino Acids

, Volume 50, Issue 1, pp 39–68 | Cite as

Thirteen decades of peptide synthesis: key developments in solid phase peptide synthesis and amide bond formation utilized in peptide ligation

  • Da’san M. M. Jaradat
Invited Review


A historical overview of peptide chemistry from T. Curtius to E. Fischer to M. Bergmann and L. Zervas is first presented. Next, the fundamentals of peptide synthesis with a focus on solid phase peptide synthesis by R. B. Merrifield are described. Immobilization strategies to attach the first amino acid to the resin, coupling strategies in stepwise peptide chain elongation, and approaches to synthesize difficult peptide sequences are also shown. A brief comparison between tert-butyloxycarbonyl (Boc)/benzyl (Bzl) strategy and 9-fluorenylmethoxycarbonyl (Fmoc)/tert-butyl (t -Bu) strategy utilized in solid phase peptide synthesis is given with an emphasis on the latter. Finally, the review focuses on the discovery and development of peptide ligation and the latest advances in this field including native amide bond formation strategies, these include the native chemical ligation, α-ketoacid–hydroxylamine ligation, and serine/threonine ligation which are the most commonly used chemoselective ligation methods that provide amide bond at the ligation site. This review provides an overview of the literature concerning the most important advances in the chemical synthesis of proteins and peptides covering the period from 1882 to 2017.


SPPS Resins Coupling reagents Difficult peptide sequences Chemoselective ligation Chemical protein synthesis 



The author gratefully acknowledges the financial support by Scientific Research Support Fund (SRSF) of Jordan within the Grant (Project MPH/2/03/2012). Furthermore, Dr. Michaela Mühlberg (Royal Society of Chemistry), Prof. Dr. Feras Alali (University of Qatar), and Eng. Rakeen Abuhanih (GMA Jordan) are thanked for careful proofreading and for the helpful discussions. The author also wishes to thank Prof. Dr. Christian P. R. Hackenberger (Leibniz—Institut für Molekulare Pharmakologie (FMP) and Humboldt Universität zu Berlin) for his valuable notes during the preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest.

Ethical standards

The manuscript does not contain any patient data or clinical studies.


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© Springer-Verlag GmbH Austria, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of ScienceAl-Balqa Applied UniversityAl-SaltJordan

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