Polyethylene glycol is a flexible, water-soluble and poorly reactive polymer. When it is attached to a peptide, the resulting molecule takes up much more volume in solution: it exceeds the kidney's filtration threshold and is partly shielded from proteases and the immune system.
It is a different strategy from lipidation, although it has the same goal: lipidation “hooks” the peptide onto the body's own albumin, whereas PEGylation makes it bigger directly. It has been used in several protein and peptide drugs to space out administration.
Its main drawbacks are that PEG can reduce receptor affinity if it is attached near the active site, and that the polymer is polydisperse (chains of different lengths), which complicates analytical characterisation.
Knowing the half-life extension strategies (PEGylation, lipidation, DAC-type albumin binding) helps explain why two analogues of the same hormone have such different half-lives.
Related terms
Learn it in depth at the Peptide University
- Half-life engineering · Module 2
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