Overview of Solid Phase Synthesis of “Difficult Peptide” Sequences

Anna K. Tickler1, John D. Wade1

1 University of Melbourne, Victoria, Australia
Publication Name:  Current Protocols in Protein Science
Unit Number:  Unit 18.8
DOI:  10.1002/0471140864.ps1808s50
Online Posting Date:  November, 2007
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

Solid‐phase peptide synthesis has contributed immeasurably to the understanding of the chemistry and biology of peptides by enabling their ready preparation in small quantities up to the ton scale. The advantages of the technology, including its simplicity, ease of operation, and general efficiency have far outweighed its limitations. However, despite the general effectiveness of the solid phase synthesis methodology, some peptides are resistant to efficient assembly and are known as “difficult peptides.” Such sequences can present serious challenges to the peptide researcher and have been the subject of considerable investigation. This phenomenon is described together with modern approaches designed to minimize or overcome this hitherto long‐standing and vexing problem. Curr. Protoc. Protein Sci. 50:18.8.1‐18.8.6. © 2007 by John Wiley & Sons, Inc.

Keywords: amino acid derivatives; “difficult peptide” sequences; secondary structure; solid phase peptide synthesis

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • The “Difficult Peptide” Sequence Phenomenon
  • Aids in the Synthesis of “Difficult Peptide” Sequences
  • Conclusions
  • Literature Cited
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   Angell, Y. and Burgess, K. 2005. Ring closure to β‐turn mimics via copper‐catalyzed azide/alkyne cycloadditions. J. Org. Chem. 70:9595‐9598.
   El‐Agnaf, O.M.A., Mahil, D.S., Patel, B.P., and Austen, B.M. 2000. Oligomerization and toxicity of β‐amyloid‐42 implicated in Alzheimer's disease. Biochem. Biophys. Res. Commun. 273:1000‐1007.
   Garcia‐Martin, F., Quintanar‐Audelo, M., Garcia‐Ramos, Y., Cruz, L.J., Gravel, C., Furic, R., Cote, S., Tulla‐Puche, J., and Albericio, F. 2006. Chemmatrix, a poly(ethylene glycol)‐based support for the solid‐phase synthesis of complex peptides. J. Comb. Chem. 8:213‐220.
   Gedye, R., Smith, F., Westaway, K., Ali, H., Baldisera, L., Laberge, L., and Rousell, J. 1986. The use of microwave‐ovens for rapid organic‐synthesis. Tetrahedron Lett. 27:279‐282.
   Giguere, R.J., Bray, T.L., Duncan, S.M., and Majetich, G. 1986. Application of commercial microwave‐ovens to organic‐synthesis. Tetrahedron Lett. 27:4945‐4948.
   Gorske, B.C., Jewell, S.A., Guerard, E.J., and Blackwell, H.E. 2005. Expedient synthesis and design strategies for new peptoid construction. Org. Lett. 7:1521‐1524.
   Horne, W.S., Yadav, M.K., Stout, C.D., and Ghadiri, M.R. 2004. Heterocyclic peptide backbone modifications in an α‐helical coiled coil. J. Am. Chem. Soc. 126:15366‐15367.
   Hyde, C., Johnson, T., Owen, D., Quibell, M., and Sheppard, R.C. 1994. Some ‘difficult sequences’ made easy. Int. J. Peptide Protein Res. 43:431‐440.
   Johnson, T., Quibell, M., and Sheppard, R.C. 1995. N,O‐bisfmoc derivatives of N‐(2‐hydroxy‐4‐methoxybenzyl)‐amino acids: Useful intermediates in peptide synthesis. J. Peptide Sci. 1:11‐25.
   Lee, T.K., Lee, S.M., Ryoo, S.J., Byun, J.W., and Lee, Y.S. 2005. Application of AM SURETM resin to solid‐phase peptide synthesis. Tetrahedron Lett. 46:7135‐7138.
   Matsushita, T., Hinou, H., Kurogochi, M., Shimizu, H., and Nishimura, S.I. 2005. Rapid microwave‐assisted solid‐phase glycopeptide synthesis. Org. Lett. 7:877‐880.
   Murray, J.K., Farooqi, B., Sadowsky, J.D., Scalf, M., Freund, W.A., Smith, L.M., Chen, J.D., and Gellman, S.H. 2005. Efficient synthesis of a beta‐peptide combinatorial library with microwave irradiation. J. Am. Chem. Soc. 127:13271‐13280.
   Murray, J.K. and Gellman, S.H. 2005. Application of microwave irradiation to the synthesis of 14‐helical beta‐peptides. Org. Lett. 7:1517‐1520.
   Nilsson, B.L., Soellner, M.B., and Raines, R.T. 2005. Chemical synthesis of proteins. Annu. Rev. Biophys. Biomol. Struct. 34:91‐118.
   Oh, K. and Guan, Z.B. 2006. A convergent synthesis of new beta‐turn mimics by click chemistry. Chem. Commun. 3069‐3071.
   Palasek, S.A., Cox, Z.J., and Collins, J.M. 2007. Limiting racemization and aspartimide formation in microwave‐enhanced fmoc solid phase peptide synthesis. J. Pept. Sci. 13:143‐148.
   Slater, M., Snauko, M., Svec, F., and Frechet, J.M.J. 2006. “Click chemistry” in the preparation of porous polymer‐based particulate stationary phases for µ‐HPLC separation of peptides and proteins. Anal. Chem. 78:4969‐4975.
   Sohma, Y., Hayashi, Y., Kimura, M., Chiyomori, Y., Taniguchi, A., Sasaki, M., Kimura, T., and Kiso, Y. 2005. The ‘O‐acyl isopeptide method’ for the synthesis of difficult sequence‐containing peptides: Application to the synthesis of Alzheimer's disease‐related amyloid beta peptide (a beta) 1‐42. J. Pept. Sci. 11:441‐451.
   Sohma, Y. and Kiso, Y. 2006. “Click peptides”‐chemical biology‐oriented synthesis of Alzheimer's disease‐related amyloid beta peptide (a beta) analogues based on the “O‐acyl isopeptide method.” Chembiochem. 7:1549‐1557.
   Stewart, J.M. and Klis, W.A. 1990. Polystyrene‐based solid phase peptide synthesis: The state of the art. In Innovation and Perspectives in Solid Phase Synthesis (R. Epton ed.) pp. 1‐9. SPCC (UK) Ltd, Birmingham, UK.
   Tickler, A.K., Barrow, C.J., and Wade, J.D. 2001. Improved preparation of amyloid‐beta peptides using DBU as Nalpha‐Fmoc deprotection reagent. J. Pept. Sci. 7:488‐94.
   Tornoe, C.W., Christensen, C., and Meldal, M. 2002. Peptidotriazoles on solid phase: [1,2,3]‐triazoles by regiospecific copper(i)‐catalyzed 1,3‐dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 67:3057‐3064.
   Wade, J.D., Mathieu, M.N., Macris, M., and Tregear, G.W. 2000. Base induced side reactions in fmoc‐solid phase peptide synthesis: Minimisation by use of piperizine as Nα‐deprotection reagent. Lett. Pept. Sci. 7:107‐112.
   Wohr, T. and Mutter, M. 1995. Pseudo‐prolines in peptide‐synthesis: Direct insertion of serine and threonine derived oxazolidines in dipeptides. Tetrahedron Lett. 36:3847‐3848.
   Zahariev, S., Guarnaccia, C., Pongor, C.I., Quaroni, L., Cemazar, M., and Pongor, S. 2006. Synthesis of ‘difficult’ peptides free of aspartimide and related products, using peptoid methodology. Tetrahedron Lett. 47:4121‐4124.
   Zinieris, N., Zikos, C., and Ferderigos, N. 2006. Improved solid‐phase peptide synthesis of ‘difficult peptides’ by altering the microenvironment of the developing sequence. Tetrahedron Lett. 47:6861‐6864.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library