Skip to main content

Advertisement

SpringerLink
Log in

Application of Dmb-Dipeptides in the Fmoc SPPS of Difficult and Aspartimide-Prone Sequences

  • Published:
International Journal of Peptide Research and Therapeutics Aims and scope Submit manuscript

Abstract

Mutter’s pseudoproline dipeptides and Sheppard’s Hmb derivatives are powerful tools for enhancing synthetic efficiency in Fmoc SPPS. They work by exploiting the natural propensity of N-alkyl amino acids to disrupt the formation of the secondary structures during peptide assembly. Their use results in better and more predictable acylation and deprotection kinetics, enhanced reaction rates, and improved yields of crude products. However, these approaches have certain limitations: pseudoproline dipeptides can only be used for sequences containing serine or threonine, and the coupling of the amino acid following the Hmb residue can be extremely difficult. To alleviate some of these shortcomings, we have prepared a range of Fmoc-Aaa-(Dmb)Gly-OH dipeptides and tested their efficacy in the synthesis of a number of challenging hydrophobic peptides. We also compared the efficiency of N-Dmb against N-Hmb backbone protection in preventing aspartimide formation in the Fmoc SPPS of peptides containing the Asp-Gly sequence.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Abedini A, Raleigh DP (2005) Incorporation of Pseudoproline derivatives allows the facile synthesis of human IAPP, a highly amyloidogenic and aggregation-prone polypeptide. Org Lett 7:693–696

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Bedford J, Carolyn BH, Johnson T, Jun W, Quibell M, Robert CS (1992) Amino acid structure and difficult sequences in solid phase peptide synthesis. Int J Pept Protein Res 40:300–307

    PubMed  CAS  Google Scholar 

  • Haack T, Mutter M (1992) Serine derived oxazolidines as secondary structure disrupting, solubilizing building blocks in peptide synthesis. Tetrahedron Lett 33:1589–1592

    Article  CAS  Google Scholar 

  • Hyde C, Johnson T, Owen D, Quibell M, Sheppard RC (1994) Some difficult sequences made easy—a study of interchain association in solid-phase peptide-synthesis. Int J Pept Protein Res 43:431–440

    PubMed  CAS  Google Scholar 

  • Jobling MF, Barrow CJ, White AR, Masters CL, Collins SJ, Cappai R (1999) The synthesis and spectroscopic analysis of the neurotoxic prion peptide 106–126: comparative use of manual Boc and Fmoc chemistry. Lett Pept Sci 6:129–134

    CAS  Google Scholar 

  • Johnson T, Quibell M, Owen D, Sheppard RC (1993) A reversible protecting group for the amide bond in peptides: use in the synthesis of difficult sequences. J Chem Soc Chem Commun 369–372

  • Kent SBH (1988) Chemical Synthesis of Peptides and Proteins. Annu Rev Biochem 57:957–989

    Article  PubMed  CAS  Google Scholar 

  • Mergler M, Dick F, Sax B, Weiler P, Vorherr T (2003) The aspartimide problem in Fmoc-based SPPS: part 1. J Pept Sci 9:36–46

    Article  PubMed  CAS  Google Scholar 

  • Milton RCD, Milton SCF, Adams PA (1990) Prediction of difficult sequences in solid-phase peptide synthesis. J Am Chem Soc 112:6039–6046

    Article  CAS  Google Scholar 

  • Narita M, Fukunaga T, Wakabayashi A, Ishikawa K, Nakano H (1984) Syntheses and properties of tertiary peptide-bond-containing polypeptides. Int J Pept Protein Res 23:306–314

    CAS  Google Scholar 

  • Nicolas E, Pujades M, Bacardit J, Giralt E, Albericio F (1997) A new approach to Hmb-backbone protection of peptides: synthesis and reactivity of N-alpha-Fmoc-N-alpha-(Hmb) amino acids. Tetrahedron Lett 38:2317–2320

    Article  CAS  Google Scholar 

  • Oliveira E, Miranda A, Albericio F, Andreu D, Paiva ACM, Nakaie CR, Tominaga M (1997) Comparative evaluation of the synthesis and purification of transmembrane peptide fragments–rat bradykinin receptor fragment 64–97 as model. J Pept Res 49:300–307

    PubMed  CAS  Google Scholar 

  • Packman LC, Quibell M, Johnson T (1994) Roles of electrospray mass-spectrometry, counterion distribution monitoring and N-(2-Hydroxy-4-Methoxybenzyl) backbone protection in peptide-synthesis. Pept Res 7:125–131

    PubMed  CAS  Google Scholar 

  • Quibell M, Owen D, Packman LC, Johnson T (1994) Suppression of piperidine-mediated side product formation for Asp(OtBu)-containing peptides by the use of N-(2-Hydroxy-4-Methoxybenzyl) (Hmb) backbone amide protection. J Chem Soc Chem Commun 2343–2344

  • Sampson WR, Patsiouras H, Ede NJ (1999) The synthesis of ‘Difficult’ peptides using 2-Hydroxy-4-methoxybenzyl or pseudoproline amino acid building blocks: a comparative study. J Pept Sci 5:403–409

    Article  PubMed  CAS  Google Scholar 

  • Schnölzer M, Alewood P, Jones A, Alewood D, Kent SBH (1992) In situ neutralization in Boc-chemistry solid phase peptide synthesis. Rapid, high yield assembly of difficult sequences. Int J Pept Protein Res 40:180–193

    PubMed  Google Scholar 

  • Simmonds RG (1996) Use of the Hmb backbone-protecting group in the synthesis of difficult sequences. Int J Pept Protein Res 47:36–41

    PubMed  CAS  Google Scholar 

  • Stewart JM, Klis WA (1990) Polystyrene-based solid phase peptide synthesis: the state-of-the-art. In: Epton E (ed) Innovations and perspectives in solid phase synthesis: peptides, polypeptides and oligonucleotides. SPCC (UK) Ltd, Birmingham, pp 1–9

    Google Scholar 

  • Tagliavini F, Prelli F, Verga L et al (1993) Synthetic peptides homologous to prion protein residues 106–147 form amyloid-like fibrils in vitro. Proc Natl Acad Sci USA 90:9678–9682

    Article  PubMed  CAS  Google Scholar 

  • Toniolo C, Bonora GM, Mutter M, Pillaib VNR (1981) linear oligopeptides, 77a) the effect of the insertion of a proline residue on the solid-state conformation of host peptides. Makromol Chem 182:1997–2005

    Google Scholar 

  • Weygand F, Steglich W, Bjarnason J, Akhtar R, Khan M (1966) Leicht abspaltbare schutzgruppen für säureamidfunktionen 1 Mitteilung. Tetrahedron Lett 7:3483–3487

    Article  Google Scholar 

  • White PD, Keyte J, Bailey K, Bloomberg G (2004) Expediting the Fmoc solid phase synthesis of long peptides through the application of dimethyloxazolidine dipeptides. J Pept Sci 10:18–26

    Article  PubMed  CAS  Google Scholar 

  • Zahariev S, Guarnaccia C, Pongor CI, Quaroni L, Cemazar M, Pongor S (2007) Application of peptoid methodology for synthesis of “Difficult” peptides free of aspartimide and related products. In: Rolka K, Rekowski P, Silberring J (eds) Peptides 2006, Proceedings of the European Peptide Symposium. Kennes International, Geneva, pp 84–85

  • Zhang L, Goldammer C, Henkel B, Zuehl F, Panhaus G, Jung G, Bayer E (1994) “Magic Mixture”, a powerful solvent system for solid-phase synthesis of “difficult sequences”. In: Epton E (ed) Innovation and perspectives in solid phase synthesis: peptides, proteins and nucleic acids—biological and biomedical applications, 3rd International Symposium. Mayflower Worldwide Ltd., Birmingham, UK, pp 711–716

Download references

Author information

Author notes

  1. J. Beythien

    Present address: Genzyme Pharmaceuticals, Liestal, Switzerland

Authors and Affiliations

  1. Genzyme Pharmaceuticals, Liestal, Switzerland

    V. Cardona & I. Eberle

  2. Polyphor, Allschwil, Switzerland

    S. Barthélémy

  3. Novabiochem, Merck Biosciences AG, Laeufelfingen, Switzerland

    J. Beythien, B. Doerner & P. Schneeberger

  4. Department of Biochemistry, University of Nottingham, Nottingham, UK

    J. Keyte

  5. Novabiochem, Merck Chemicals Ltd, Beeston, UK

    P. D. White

Authors
  1. V. Cardona
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. Eberle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Barthélémy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Beythien
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. Doerner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. Schneeberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Keyte
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. D. White
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. D. White.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cardona, V., Eberle, I., Barthélémy, S. et al. Application of Dmb-Dipeptides in the Fmoc SPPS of Difficult and Aspartimide-Prone Sequences. Int J Pept Res Ther 14, 285–292 (2008). https://doi.org/10.1007/s10989-008-9154-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10989-008-9154-z

Keywords

Search

Navigation