The covalent attachment of methoxy-poly(ethylene glycol) (mPEG) is a well established strategy used to improve the pharmaceutical
properties of several biomolecules. Since the pioneering work of Abuchovsky, PEGylation has emerged as a powerful technology
of significant relevance, not only for the development of new and better drugs, but also for application in material science. Peptides
and proteins are the most traditional targets for PEGylation due to their intense and diverse biotechnological applications. The terminal
amino group, as well as the ε-amino group of lysine and the thiol group of cysteine, are all well known nucleophilic sites that have traditionally
been used to couple peptides and proteins to mPEG derivatives. Advances in the methods for preparation of the mPEG starting
materials, together with a careful selection of new mPEG functional end-groups have allowed new reactive mPEGs to emerge, which
show narrow polydispersity and controlled reactivity, providing more homogeneous conjugates. In the last few years the trend has moved
towards site-selective, reversible and enzymatic PEGylation using a new generation of tailor-made reagents and strategies. The main goal
of this article is to present some of the most relevant achievements obtained in the PEGylation of peptides and proteins. The chemistry
underlying the current methods used for the preparation of mPEG reagents, as well as the chemistry involved in the PEGylation reactions
are presented in detail, in order of stimulating the synthetic and polymer chemist to turn their attention in this fascinating multi and
interdisciplinary field of research.
Keywords: PEGylation, Poly(ethylene glycol), PEG reagents, Conjugation, Protein PEGylation, Controlled drug release, Activated PEG.
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