Skip to main content

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

Poly(ethylene glycol) (PEG) derivatives are the first choice of the water soluble, biocompatible polymers on hand for conjugation to proteins and polypeptides. This chapter deals with the PEG reagents that are available for the preparation of bioconjugates. The opportunities of different reactive groups on PEG are described and their different activities against the functional moieties of the amino acids are illustrated. Some attention is also given to the modification of the PEG backbone to increase its loading capacity and to eventually modify the stability of the conjugating bonds.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Properties and Use of Polyethylene Glycol (1977), Hoechst Polyglycol s Katalog

    Google Scholar 

  2. Zalipsky S (1995) Functionalized Poly(ethylene glycol) for Preparation of Biologically Relevant Conjugates. Bioconjugate Chem., 6:150–165

    Article  CAS  Google Scholar 

  3. Harris JM (1985) Laboratory Synthesis of Polyethylene Glycol Derivatives. JMS-Rev. Macromol. Chem. Phys., C25:325–373

    CAS  Google Scholar 

  4. Lundblad RL (2005) Chemical Reagents for Protein Modification 3rd Edit. CRC Press

    Google Scholar 

  5. Pedder S (2001) PEGASYS®: A true once-a-week antiviral. Annual Meeting, American Association of the Study of Liver Diseases (AASLD), Dallas, TX

    Google Scholar 

  6. Sartore L, Caliceti P, Schiavon O, Monfardini C, Veronese FM (1991) Accurate evaluation method of the polymer content in monomethoxy poly(ethylene glycol)modified proteins based on amino acid analysis. Appl. Biochem. Biotechnol., 31:213–222.

    Article  CAS  PubMed  Google Scholar 

  7. Zalipsky S, Lee C (1992) Use of functionalized poly(ethylene glycol) s for modification of polypeptides. In: JM Harris, S Zalipsky (Eds.), Polyethylene Glycol Chemistry, Biotechnical and Biomedical Applications, Plenum, New York, pp. 347–370

    Google Scholar 

  8. Francis GE, Fisher D, Delgado C, Malik F, Gardiner A, Neale D (1998) PEGylation of cytokines and other therapeutic proteins and peptides: the importance of biological optimization of coupling techniques. Int. J. Hematol., 68:1–18

    Article  CAS  PubMed  Google Scholar 

  9. Harris JM, Herati RM (1993) Preparation and use of poly-ethylene glycol propionaldehyde. US Patent 5,252,714

    Google Scholar 

  10. Kinstler OB, Brems DN, Lauren SL (1996) Characterization and stability of N-terminally PEGylated rhG-CSF. Pharm Res., 13:996–1002

    Article  CAS  PubMed  Google Scholar 

  11. Kinstler OB, Gabriel NE, Farrar CE, DePrince RB (1999) N-terminally chemically modified protein compositions and methods, US Patent 5,985,265

    Google Scholar 

  12. Edwards CK (1993) PEGylated recombinant human soluble tumor necrosis factor receptor type I (rHu-sTNF-RI): A novel high-affinity TNF receptor designed for chronic inflammatory diseases. Ann. Rheum. Dis., 58:173–181

    Google Scholar 

  13. Zalipsky S, Seltzer R, Menon-Rudolph S (1992) Evaluation of a new reagent for covalent attachment of polyethylene glicol to proteins. Biotechnol. Appl. Biochem., 15:100–114

    CAS  PubMed  Google Scholar 

  14. Miron T, Wilchek M (1993) A simplified method for the preparation of succinimidyl carbonate polyethylene glycol for coupling to proteins. Bioconjug. Chem., 4:568–569

    Article  CAS  PubMed  Google Scholar 

  15. Dolence EK, Hu C, Tsang R, Sanders CG, Osaki S (1997) Electrophilic polyethylene oxides for the modification of polysaccharides, polypeptides (proteins) and surfaces. US Patent 5,650,234

    Google Scholar 

  16. Veronese FM, Largajolli R, Boccu E, Benassi CA, Schiavon O (1985) Activation of monomethoxy poly(ethylene glycol) by phenylchloroformate and modification of ribonuclease and superoxide dismutase. Appl. Biochem. Biotechnol., 11:141–152

    Article  CAS  PubMed  Google Scholar 

  17. Beauchamp CO, Gonias SL, Menapace DP, Pizzo SV (1983) A new procedure for the synthesis of polyethylene glycolglycol protein adducts, effects on function, receptor recognition and clearance of superoxide dismutase, lactoferrin and a2-macro-globulin. tAnal. Biochem., 131:25–33

    Article  CAS  PubMed  Google Scholar 

  18. Carter MC, Meyerhoff ME (1985) Instability of succinyl ester linkages in 029-monosuccinyl cyclic AMP-protein conjugates at neutral pH. J. Immunol. Methods, 81:245–257

    Article  CAS  PubMed  Google Scholar 

  19. Abuchowski J, Kazo GM, Verhoest CR (1984) Cancer therapy with chemically modified enzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates. Cancer Biochem. Biophys., 7:175–186

    CAS  PubMed  Google Scholar 

  20. Zalipsky S, Barany G (1986) Preparation of polyethylene glycol derivatives with two different functional groups at the termini. Polym. Preprints, 27:1–2

    CAS  Google Scholar 

  21. Zalipsky S, Barany G (1990) Facile synthesis of α-hydroxy-ω-carboxymethylpolyethylene oxide. J. Bioact. Compat. Polym., 5:227–231

    Article  CAS  Google Scholar 

  22. Harris JM, Kozlowski A (1997) Polyethylene glycol and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications. US Patent 5,672,662

    Google Scholar 

  23. Sartore L, Caliceti P, Schiavon O, Veronese FM (1991) Enzyme modification by MPEG with amino acid or peptide as spacer arm. Appl. Biochem. Biotechnol., 27:55–63

    Article  Google Scholar 

  24. Veronese FM, Saccà B, Polverino de Laureto P, Sergi M, Caliceti P, Schiavon O (2001) New PEGs for peptide and protein modification, suitable for identification of the PEGylation site. Bioconjugate Chem., 12:62–70

    Article  CAS  Google Scholar 

  25. Goodson RJ, Katre NV (1990) Site-directed pegylation of recomproteins binant interleukin-2 at its glycosylation site. Biotechnology, 8:343–346

    Article  CAS  PubMed  Google Scholar 

  26. Kogan TP (1992) The synthesis of substituted methoxy-polymer (ethylene glycol) derivatives suit able for selective protein modification. Synth. Commun., 22:2417–2424

    Article  CAS  Google Scholar 

  27. Morpurgo M, Veronese FM, Kachensky D, Harris JM (1976) Preparation and characterization of poly(ethylene glycol) vinyl sulfone. Bioconjug. Chem., 7:363–368

    Article  Google Scholar 

  28. Woghiren C, Sharma B, Stein S (1993) Protected thiol-polycoupling ethylene glycol: a new acti vated polymer for reversibile protein modification. Bioconjug. Chem., 4:314–318

    Article  CAS  PubMed  Google Scholar 

  29. Gard FRN (1972) Carboxymethylation. Methods Enzymol., B25:424–449

    Article  Google Scholar 

  30. Greenwald RB, Pendri A, Bolikal D (1995) Highly soluble taxol derivatives: 7-polyethylene glycol carbamates and carbonates. J. Org. Chem., 60:331–336

    Article  CAS  Google Scholar 

  31. Pace G, Veronese FM, Bonora GM (1999) Synthesis and reactivity of high-molecular mass phosphorylated poly(ethylene glycol). Reactive & Functional Polimers, 41:141–148

    Article  CAS  Google Scholar 

  32. De Frees S, Wang ZG, Xing R (2006) GlycoPEGylation of recombinant therapeutic proteins produced in Escherichia coli. Giycobiology 16:833–843

    Article  Google Scholar 

  33. Zalipski S, Menon-Rudolph S (1997) Hydrazide derivatives of poly(ethylene glycol) and their bioconjugates. Poly(ethylene glycol) chemistry and biological applications. ACS Symp Ser, 680:318–341

    Article  Google Scholar 

  34. Yankeelov Jr AJA (1972) Modification of arginine by diketones. Methods Enzymol., B25:566–584

    Article  Google Scholar 

  35. Maeda H, Kai Y, Ono K (1989) Polyethylene glycol derivatives, modified, peptides and production thereof. E.P. 0.340.741

    Google Scholar 

  36. Sato H (2002) Enzymatic procedure for site-specific PEGylation of proteins, Adv. Drug Deliv. Rev., 54:487–504

    Article  CAS  PubMed  Google Scholar 

  37. Fontana A, Spolaore B, Mero A, Veronese FM (2008) Site-specific modification and PEGylation of pharmaceutical proteins mediated by transglutaminase, Adv. Drug Deliv. Rev. 60:13–28

    Article  CAS  PubMed  Google Scholar 

  38. Monfardini C, Schiavon O, Caliceti P, Morpurgo M, Harris JM, Veronese FM (1995) A Branched Monomethoxypoly(ethylene glycol) for Protein Modification, Bioconjugate Chem., 6:62–69

    Article  CAS  Google Scholar 

  39. Schiavon O, Pasut G, Moro S, Orsolini P, Guiotto A, Veronese FM (2004) PEG-Ara C conjugation for controlled release. Eur. J. Med. Chem., 39(2):123–133

    Article  CAS  PubMed  Google Scholar 

  40. Pasut G, Scaramuzza S, Schiavon O, Mendichi R, Veronese FM (2005) PEG-epirubicin conjugates with high drug loading. J. of Bioactive and Compatible Polymers 20:213–230

    Article  CAS  Google Scholar 

  41. Liu X-M, Thakur A, Wang D (2007) Efficient Synthesis of Linear Multifunctional Poly(ethylene glycol) by Copper(I)-Catalyzed Huisgen 1,3-Dipolar Cycloaddition. Biomacromolecules, 8:2653–2658

    Article  CAS  PubMed  Google Scholar 

  42. Ballico M, Drioli S, Bonora GM (2005) MultiPEG: high molecular weight multifunctional poly(ethylen glycol)s assembled by a dendrimer-like approach. EJOC, 2064–2067

    Google Scholar 

  43. Drioli S, Bonora GM, Ballico M (2008) Synthesis and characterization of new multifunctional high-molecular weight PEG derivatives (MultiPEG)s. The Open Organic Chemistry Journal 2:17–25

    Article  CAS  Google Scholar 

  44. Harris JM, Chess RB (2003) Effect of PEGylation on Pharmaceuticals. Nature Reviews Drug Discovery 2:214–221

    Article  CAS  PubMed  Google Scholar 

  45. Roberts MJ, Bentley MD, Harris JM (2002) Chemistry for peptide and protein PEGylation. Adv. Drug Del. Rev. 54:459–476

    Article  CAS  Google Scholar 

  46. Zhao X, Harris JM (1997) Novel degradable poly(ethylene glycol) esters for drug delivery. In: JM Harris, S Zalipsky (eds): Poly(ethylene glycol) chemistry and biological applications. American Chemical Society, Washington, DC, 458–472

    Chapter  Google Scholar 

  47. Testa B, Mayer JM (eds): (2003) Hydrolysis in drug and prodrug metabolism: Chemistry, biochemistry, and enzymology. Verlag Helvetica Chimica Acta, Wiley-VCH, Switzerland

    Google Scholar 

  48. Zalipsky S, Qazen M, Walker II JA, Mullah N, Quinn YP, Huang SK (1999) New detachable poly(ethylene glycol) conjugates: Cysteine-cleavable lipopolymers regenerating natural phospholipids, diacyl phosphatidylethanolamine. Bioconjug. Chem. 10:703–707

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Birkhäuser Verlag/Switzerland

About this chapter

Cite this chapter

Bonora, G.M., Drioli, S. (2009). Reactive PEGs for protein conjugation. In: Veronese, F.M. (eds) PEGylated Protein Drugs: Basic Science and Clinical Applications. Milestones in Drug Therapy. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8679-5_3

Download citation

Publish with us

Policies and ethics