Solid Phase Peptide Synthesis History HEADING_TITLE

Introduction

Introduction
The purpose of this guide is to provide practical information for planning and executing successful solid phase peptide syntheses.  The procedures included were found to be generally applicable, but they may not be optimal in every synthesis.  Various factors, including the production scale, peptide sequence and length of the peptide might require modification of these procedures for best results.  In critical applications, if time and materials permit, small-scale tests are recommended.  Before preparing any peptide on a large scale, it should be synthesized on a small scale first to identify and rectify potential problems.
Many books covering the theory and practice of solid phase synthesis have been published.  The following are a few of the recent publications.
Methods of Enzymology, 289, Solid Phase Peptide Synthesis, (G. B. Fields Ed.) Academic Press, 1997.
Chemical Approaches to the Synthesis of Peptides and Proteins, P. Lloyd-Williams, F. Albericio, and E. Giralt Eds), CRC Press, 1997.
Fmoc Solid Phase Peptide Synthesis, A Practical Approach, (W. C. Chan, P. D. White Eds), Oxford University Press, 2000.
Solid Phase Synthesis, A Practical Guide, (S. F. Kates, F Albericio Eds), Marcel Dekker, 2000.
P. Seneci, Solid-Phase Synthesis and Combinatorial Technologies, John Wiley & Sons, 2000.
Houben-Weyl E22a, Synthesis of Peptides and Peptidomimetics (M. Goodman, Editor-in-chief, A. Felix, L.  Moroder, C. Tmiolo Eds), Thieme, 2002, p. 665ff.
N. L. Benoiton, Chemistry of Peptide Synthesis, CRC Press, 2005.
J. Howl, Methods in Molecular Biology, 298, Peptide Synthesis and Applications, (J. Howl Ed) Humana Press, 2005.
Amino Acids, Peptides and Proteins in Organic Chemistry, Volume 3, Building Blocks, Catalysts and Coupling Chemistry, (A. B. Hughs, Ed.) Wiley-VCH, 2011.Introductio

The purpose of this guide is to provide practical information for planning and executing successful solid phase peptide syntheses.  The procedures included were found to be generally applicable, but they may not be optimal in every synthesis.  Various factors, including the production scale, peptide sequence and length of the peptide might require modification of these procedures for best results.  In critical applications, if time and materials permit, small-scale tests are recommended.  Before preparing any peptide on a large scale, it should be synthesized on a small scale first to identify and rectify potential problems.


Many books covering the theory and practice of solid phase synthesis have been published.  The following are a few of the recent publications.

Methods of Molecular Biology, 35, Peptide Synthesis Protocols, (M. W. Pennington and B. M. Dunn Eds), Springer, 1994.

Methods of Enzymology, 289, Solid Phase Peptide Synthesis, (G. B. Fields Ed.), Academic Press, 1997.

Chemical Approaches to the Synthesis of Peptides and Proteins, (P. Lloyd-Williams, F. Albericio, and E. Giralt Eds), CRC Press, 1997.

Fmoc Solid Phase Peptide Synthesis, A Practical Approach, (W. C. Chan, P. D. White Eds), Oxford University Press, 2000.

Solid Phase Synthesis, A Practical Guide, (S. F. Kates, F Albericio Eds), Marcel Dekker, 2000.

P. Seneci, Solid-Phase Synthesis and Combinatorial Technologies, John Wiley & Sons, 2000.

Synthesis of Peptides and Peptidomimetics (M. Goodman, Editor-in-chief, A. Felix, L.  Moroder, C. Tmiolo Eds), Thieme, 2002.

N. L. Benoiton, Chemistry of Peptide Synthesis, CRC Press, 2005.

Methods in Molecular Biology, 298, Peptide Synthesis and Applications, (J. Howl Ed) Humana Press, 2005.

Amino Acids, Peptides and Proteins in Organic Chemistry, Volume 3, Building Blocks, Catalysts and Coupling Chemistry, (A. B. Hughs, Ed.) Wiley-VCH, 2011.

Brief History of Solid Phase Peptide Synthesis (SPPS)

Bruce Merrifield developed, and was awarded the Nobel Prize for, solid phase peptide synthesis.  By anchoring the C-terminal amino acid of the peptide to be synthesized to an insoluble resin support, he was able to use reagents in large excess to drive reactions to completion, then cleave the peptide from the support in relatively pure form.  Utilizing a resin support also allowed him to automate the peptide synthesis process.  These advances made it practical to synthesize larger, more complex peptides.  The easy availability of synthetic peptides has revolutionized research in biology, biochemistry, microbiology, medicinal chemistry and new drug development.

Some of the significant events are listed below:

1963 1963 Merrifield developed solid phase peptide synthesis on crosslinked polystyrene beads.
1964 1964 Merrifield introduces the Boc/Bzl protection scheme in peptide synthesis.
1967 1967 Sakakibara introduces HF cleavage.
1968 First automated solid phase synthesizer.
1970 1970 Pietta and Marshall introduce BHA resin for preparing peptide amides, Carpino and Han introduce the base labile Fmoc protecting group.
1973 1973 Wang develops p-alkoxybenzyl alcohol resin (Wang resin).
1976 1976 Burgus and Rivier utilize preparative reverse phase HPLC to purify peptides synthesized by solid phase methodology.
1977 1977 Barany and coworkers develop the concept of orthogonal protection.
1978 1978 Fmoc/tBu strategy utilizing Wang resin is developed by Meienhofer and coworkers.
1983 First production solid phase peptide synthesizer with preactivation of amino acids.
1985 Simultaneous parallel peptide synthesis, synthesis of peptide libraries.
1987 Rink introduces a TFA labile resin (Rink resin) for preparing peptide amides by Fmoc protocols, Sieber introduces xanthenyl linker (Sieber resin) for preparing fully protected peptide amides by Fmoc protocols, First commercial multiple peptide synthesizer
1988 First commercial large-scale synthesizer, Barlos and coworkers introduce 2-Chlorotritylchloride resin for preparing fully protected peptide acids by Fmoc protocols, Introduction of split-mix synthesis for preparation of large combinatorial peptide libraries.
1992 Kent and Alewood develop the Fast Boc protocol.
1994 Kent introduces native chemical ligation for synthesis of proteins and large peptides.
1996 Pseudoprolines are introduced for the synthesis of difficult peptides
2000 Verdine and Schafmeister introduce stapled peptides as potential drug leads.
2003 Stepwise preparation of long peptides (approximately 100 AA) by Fmoc protocols.
2007 Convergent chemical synthesis of a 203 residue "Covalent Dimer" of HIV-1 protease enzyme using native chhemical ligation methods.