Skip to main content

Linkers, Resins, and General Procedures for Solid-Phase Peptide Synthesis

  • Protocol
  • First Online:
Peptide Synthesis and Applications

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1047))

Abstract

This chapter describes the basic protocols for solid-phase peptide synthesis using the Fmoc group as the N α-protecting group (Fmoc-SPPS). The chapter introduces resins and their handling, choice of linkers, and the most common methods for peptide chain assembly. The proper choice of resins and linkers for solid-phase synthesis is a key parameter for successful peptide synthesis. This chapter provides an overview of the most common and useful resins and linkers for the synthesis of peptides with C-terminal amides, carboxylic acids, and more. The chapter finishes with robust protocols for general solid-phase peptide synthesis, i.e., the standard operations.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hudson D (1999) Matrix assisted synthetic transformations: a mosaic of diverse contributions. I. The pattern emerges. J Comb Chem 1:333–360

    Article  PubMed  CAS  Google Scholar 

  2. Hudson D (1999) Matrix assisted synthetic transformations: a mosaic of diverse contributions. II. The pattern is completed. J Comb Chem 1:403–457

    Article  PubMed  CAS  Google Scholar 

  3. Merrifield RB (1963) Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J Am Chem Soc 85:2149–2154

    Article  CAS  Google Scholar 

  4. Fields GB, Noble RL (1990) Solid-phase peptide-synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Int J Pept Protein Res 35:161–214

    Article  PubMed  CAS  Google Scholar 

  5. Rapp W, Zhang L, Habich R, Bayer E (1989) in Peptides 1988 (Eds. Jung G and Bayer E), de Gruyter, Berlin, p. 199

    Google Scholar 

  6. Bayer E (1991) Towards the chemical synthesis of proteins. Angew Chem Int Ed 30:113–129

    Article  Google Scholar 

  7. Meldal M (1992) Pega: a flow stable polyethylene glycol dimethyl acrylamide copolymer for solid phase synthesis. Tetrahedron Lett 33:3077–3080

    Article  CAS  Google Scholar 

  8. Garcia-Martin F, Quintanar-Audelo M, Garcia-Ramos Y, Cruz LJ, Gravel C, Furic R, Cruz S, Tulla-Puche J, Albericio F (2006) ChemMatrix, a poly(ethylene glycol)-based support for the solid-phase synthesis of complex peptides. J Comb Chem 8:213–220

    Article  PubMed  CAS  Google Scholar 

  9. Songster MF, Barany G (1997) Solid-phase peptide synthesis. In: Fields GB (ed) Methods in enzymology. Academic, San Diego, pp 126–174

    Google Scholar 

  10. Guillier F, Orain D, Bradley M (2000) Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem Rev 100:2091–2158

    Article  PubMed  CAS  Google Scholar 

  11. Rink H (1987) Solid phase synthesis of protected peptide fragments using a trialkoxy-diphenyl-methylester resin. Tetrahedron Lett 28:3787–3790

    Article  CAS  Google Scholar 

  12. Bray B (2003) Large-scale manufacture of peptide therapeutics by chemical synthesis. Nat Rev Drug Discov 2:587–593

    Article  PubMed  CAS  Google Scholar 

  13. Camarero J, Hackel BJ, de Yoreo JJ, Mitchell AR (2004) Fmoc-based synthesis of peptide α-thioesters using an aryl hydrazine support. J Org Chem 69:4145–4151

    Article  PubMed  CAS  Google Scholar 

  14. Woo Y-H, Mitchell AR, Camarero JA (2007) The use of aryl hydrazide linkers for the solid phase synthesis of chemically modified peptides. Int J Pept Res Ther 13:181–190

    Article  CAS  Google Scholar 

  15. Jensen KJ, Alsina J, Songster M, Vagner J, Albericio F, Barany G (1998) Backbone amide linker (BAL) strategy for solid-phase synthesis of C-terminal-modified cyclic peptides. J Am Chem Soc 120:5441–5452

    Article  CAS  Google Scholar 

  16. Boas U, Brask J, Christensen J, Jensen KJ (2002) The ortho backbone amide linker (o-BAL) is an easily prepared and highly acid-labile handle for solid-phase synthesis. J Comb Chem 4:223–228

    Article  PubMed  CAS  Google Scholar 

  17. Brask J, Albericio F, Jensen KJ (2003) Fmoc solid-phase synthesis of peptide thioesters by masking as trithioortho esters. Org Lett 5:2951–2953

    Article  PubMed  CAS  Google Scholar 

  18. García-Ramos Y, Parodís-Bas M, Tulla-Puche J, Albericio F (2010) ChemMatrix® for complex peptides and combinatorial chemistry. J Pept Sci 16:375–378

    Article  Google Scholar 

  19. Albericio F, Barany G (1987) An acid-labile anchoring linkage for solid-phase synthesis of C-terminal peptide amides under mild conditions. Int J Pept Protein Res 30:206–216

    Article  PubMed  CAS  Google Scholar 

  20. Albericio F, Kneib-Cordonier N, Biancalana S, Gera L, Masada RI, Hudson D, Barany G (1990) Preparation and application of the 5-(4-(9-fluorenylmethyloxycarbonyl)aminomethyl-3,5-dimethoxyphenoxy)-valeric acid (PAL) handle for the solid-phase synthesis of C-terminal peptide amides under mild conditions. J Org Chem 55:3730–3743

    Article  CAS  Google Scholar 

  21. Valeur E, Bradley M (2009) Amide bond formation: beyond the myth of coupling reagents. Chem Soc Rev 38:606–631

    Article  PubMed  CAS  Google Scholar 

  22. Tofteng AP, Pedersen SL, Staerk D, Jensen KJ (2012) Effect of residual water and microwave heating on the half-life of the reagents and reactive intermediates in peptide synthesis. Chem Eur J 18:9024–9031

    Article  PubMed  Google Scholar 

  23. Ball HL, Mascagni P (1995) N-(2-chlorobenzyloxycarbonyloxy)-succinimide as a terminating agent for solid-phase peptide synthesis: application to a one-step purification procedure. Lett Pept Sci 2:49–57

    Article  CAS  Google Scholar 

  24. Palasek SA, Cox ZJ, Collins JM (2007) Limiting racemization and aspartimide formation in microwave-enhanced Fmoc solid phase peptide synthesis. J Pept Sci 13:143–148

    Article  PubMed  CAS  Google Scholar 

  25. Kaiser E, Colescott RL, Bossinger CD, Cook PI (1970) Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal Biochem 34:595–598

    Article  PubMed  CAS  Google Scholar 

  26. Information on swelling is available from different distributors (December 2012) http://www.rapp-polymere.com, http://www.pcasbiomatrix.com, http://www.merckmillipore.com

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media, New York

About this protocol

Cite this protocol

Shelton, P.T., Jensen, K.J. (2013). Linkers, Resins, and General Procedures for Solid-Phase Peptide Synthesis. In: Jensen, K., Tofteng Shelton, P., Pedersen, S. (eds) Peptide Synthesis and Applications. Methods in Molecular Biology, vol 1047. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-544-6_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-62703-544-6_2

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-543-9

  • Online ISBN: 978-1-62703-544-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics