, Volume 26, Issue 4, pp 209–215 | Cite as

Site-Specific PEGylation of Therapeutic Proteins via Optimization of Both Accessible Reactive Amino Acid Residues and PEG Derivatives

  • Chun Zhang
  • Xiao-lan Yang
  • Yong-hua Yuan
  • Jun Pu
  • Fei Liao
Current Opinion


Modification of accessible amino acid residues with poly(ethylene glycol) [PEG] is a widely used technique for formulating therapeutic proteins. In practice, site-specific PEGylation of all selected/engineered accessible nonessential reactive residues of therapeutic proteins with common activated PEG derivatives is a promising strategy to concomitantly improve pharmacokinetics, allow retention of activity, alleviate immunogenicity, and avoid modification isomers. Specifically, through molecular engineering of a therapeutic protein, accessible essential residues reactive to an activated PEG derivative are substituted with unreactive residues provided that protein activity is retained, and a limited number of accessible nonessential reactive residues with optimized distributions are selected/introduced. Subsequently, all accessible nonessential reactive residues are completely PEGylated with the activated PEG derivative in great excess. Branched PEG derivatives containing new PEG chains with negligible metabolic toxicity are more desirable for site-specific PEGylation. Accordingly, for the successful formulation of therapeutic proteins, optimization of the number and distributions of accessible nonessential reactive residues via molecular engineering can be integrated with the design of large-sized PEG derivatives to achieve site-specific PEGylation of all selected/engineered accessible reactive residues.


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Copyright information

© Springer International Publishing AG 2012

Authors and Affiliations

  • Chun Zhang
    • 1
  • Xiao-lan Yang
    • 1
  • Yong-hua Yuan
    • 1
  • Jun Pu
    • 1
  • Fei Liao
    • 1
  1. 1.Unit for Analytical Probes and Protein Biotechnology, Key Laboratory of Medical Laboratory Diagnostics of the Education Ministry, College of Laboratory MedicineChongqing Medical UniversityDaping, Yuzhong DistrictChina

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