Solid-Phase Peptide Synthesis (SPPS)

Solid-Phase Peptide Synthesis (SPPS) is a method for synthesizing peptides using a solid support resin. Compared to other techniques, like liquid-phase peptide synthesis and recombinant peptide synthesis, solid-phase peptide synthesis is faster, more versatile, and allows for sequence specific modifications. Additionally, post-synthesis modifications can be performed easily. This page offers a variety of scientific articles that detail different aspects of the method. This includes the early development of SPPS, general background knowledge overviewing the method and useful tips for researchers, information on cleavage cocktails used for the cleavage of the peptide from resin, and some extra articles related to some of the reagents and resins utilized within the PPMC. For those that would like to learn more, stay tuned for the training videos for our CEM Liberty Blue and Gyros Protein Technologies PurePep Chorus peptide synthesizers.

Early Developments

Robert B. Merrifield developed and was awarded the Nobel Prize for SPPS in 1963. From that point, a variety of developments have been made to the chemistry, resins, and reagents to increase peptide yields, as well as automate the process. This section contains scientific articles that were seminal in the development of SPPS, as well as the development of Fmoc-based SPPS. These articles are in chronological order.

Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide

Robert B. Merrifield

J. Am. Chem. Soc., 85 2149-2154 (1963).

DOI: 10.1021/ja00897a025

Solid-Phase Peptide Synthesis Using Mild Base Cleavage Nα-Fluorenylmethoxycarbonylamino Acids, Exemplified by a Synthesis of Dihydrosomatostatin

Chi-Deu Chang, Johannes Meienhofer

Int. J. Pept. Protein Res., 11 246-249 (1978).

DOI: 10.1111/j.1399-3011.1978.tb02845.x

A Mild Procedure for Solid Phase Peptide Synthesis: Use of Fluorenylmethoxycarbonylamino-Acids

E. Atherton, Hazel Fox, Diana Harkiss, C. J. Logan, C. Sheppard, B. J. Williams

J. Chem. Soc., Chem. Commun., 13 537-539 (1978).

DOI: 1978/c3/c39780000537

Concept and Early Development of Solid-Phase Peptide Synthesis

Robert B. Merrifield

Methods Enzymol., 289 3-13 (1997).

DOI: 10.1016/s0076-6879(97)89040-4

General Background

This section contains scientific articles that overview SPPS. The most useful articles are listed first.

Methods and Protocols of Modern Solid Phase Peptide Synthesis

Muriel Amblard, Jean-Alain Fehrentz, Jean Martinez, Gilles Subra

Mol. Biotechnol., 33 239-254 (2006).

DOI: 10.1385/mb:33:3:239

Solid Phase Peptide Synthesis Utilizing 9-Fluorenylmethoxycarbonyl Amino Acids

Gregg B. Fields, Richard L. Noble

Int. J. Pept. Protein Res., 35 161-214 (1990).

DOI: 10.1111/j.1399-3011.1990.tb00939.x

Some Mechanistic Aspects on Fmoc Solid Phase Peptide Synthesis

Diego Arantes Teixeira Pires, Marcelo Porto Bemquerer, Claudia Jorge do Nascimento

Int. J. Pept. Protein Res., 20 53-69 (2014).

DOI: 10.1007/s10989-013-9366-8

Fmoc Solid-Phase Peptide Synthesis in Peptide Antibodies: Methods and Protocols

Paul R. Hansen, Alberto Oddo

Springer, 33-50 (2014).

DOI: 10.1007/978-1-4939-2999-3_5

Cleavage Cocktails

This section contains scientific articles that first utilized the specified cleavage cocktail. Within the PPMC, we often use Reagent B for cleaving our peptides from resin. For more information about selecting a cleavage cocktail, see the Cleavage Cocktail Selection page.

Reagent B

Optimization of Solid-Phase Synthesis of [Ala8]-Dynorphin A

Nuria A. Sole, George Barany

J. Org. Chem., 57 5399-5403 (1992).

DOI: 10.1021/jo00046a022

Reagent H

A Cleavage Cocktail for Methionine-Containing Peptides

H. Huang, Dallas L. Rabenstein

Pept. Res., 53 548-553 (1999).

DOI: 10.1034/j.1399-3011.1999.00059.x

Reagent I

C-Terminal N-Alkylated Peptide Amides Resulting From the Linker Decomposition of the Rink Amide Resin. A New Cleavage Mixture Prevents Their Formation

Panagiotis Stathopoulos, Serafim Papas, Vassilios Tsikaris

J. Pept. Sci., 12 227-232 (2006).

DOI: 10.1002/psc.706

Reagent K

A Cleavage Method Which Minimizes Side Reactions Following Fmoc Solid Phase Peptide Synthesis

David S. King, Cynthia G. Fields, Gregg B. Fields

Int. J. Pept. Protein Res., 36 255-266 (1990).

DOI: 10.1111/j.1399-3011.1990.tb00976.x

Reagent L

Solid-Phase Precipitation and Extraction, A New Separation Process Applied to the Isolation of Synthetic Peptides

A. G. Bonner, L. M. Udell, W. A. Creasey, S. R. Duly, R. A. Laursen

Pept. Res., 57 48-58 (2001).

DOI: 10.1034/j.1399-3011.2001.00801.x

Reagent M

Convergent Solid Phase Peptide Synthesis IV.: Synthesis of the 35–43 and 32–34 Protected Segments of the Toxin II of Androctonus Australis Hector

A. Grandas, E. Pedroso, E. Giralt, C. Granier, J. Van Rietschoten

Tetrahedron, 42 6703-6711 (1986).

DOI: 10.1016/S0040-4020(01)82111-6

Reagent R

Practical Protocols for Stepwise Solid-Phase Synthesis of Cysteine-Containing Peptides

Y. M. Angell, J. Alsina, F. Albericio, G. Barany

Pept. Res., 60 292-299 (2002).

DOI: 10.1034/j.1399-3011.2002.02838.x

Extra

This section provides scientific articles that are relevant to some of the methods and protocols utilized within the PPMC.

Oxyma: An Efficient Additive for Peptide Synthesis to Replace the Benzotriazole-Based HOBt and HOAt with a Lower Risk of Explosion

Ramon Subirós-Funosas, Rafel Prohens, Rafael Barbas, Ayman El-Faham, Fernando Albericio

Chem. Eur. J., 15 9394-9403 (2009).

DOI: 10.1002/chem.200900614

Solid-Phase Synthesis of Protected Peptide Fragments Using a Trialkoxy-Diphenyl-Methylester Resin

Hans, Rink

Tetrahedron Lett., 28 3787-3790 (1987).

DOI: 10.1016/S0040-4039(00)96384-6