PEG with the reactive motifs of enzymes. Commonly,

PEG is the most commonly used polymer for the preparation of polymer–enzyme conjugates. Covalently attaching PEG to the enzymes, also termed as PEGylation, is generally achieved by reacting PEG with the reactive motifs of enzymes. Commonly, PEGylation is achieved through reacting the ?-amino groups of lysine residues. This process often results in the formation of conjugated isomers containing various PEG chains attached at different sites 57, and further purification process is required for FDA approval. To circumvent this limitation, site-specific PEGylation reactions have also been developed 80, such as the methods of N-terminal PEGylation and cysteine-specific PEGylation, where the conjugation is occurred at the N-terminal ?-amino groups and the residue cysteines (or cleaved disulfide bond), respectively 81–83. Other site-specific PEGylation methods were also developed, such as conjugating PEG–alkylamine reagent onto gluta- mine residues by transglutaminase 84,85, and reacting (sialic acid)- PEG with the hydroxyl groups of a glycosylated protein 86. These site-specific strategies lead to more defined conjugating structure, facil- itating their transition for clinic use. The shielding effect of PEG is mainly attributed from its hydrogen bonding with water, though the backbone of the molecule is hydropho- bic. When dispersed in aqueous solution, the PEG chains form hydrogen bonds with the surrounding water molecules 87. Such hydrated layers effectively shield the enzymes from their surrounding, affording the enzymes with improved bioavailability, prolonged circulation time, and reduced immunogenicity and toxicity (Fig. 3). Consistently, PEG with longer chain length and higher density offers longer circulation life. In addition, PEG chain architecture also influences the pharmacoki- netics of PEGylated enzymes, and branched PEG generally exhibits longer circulation half life than linear ones with similar molecular weight 88. However, such shielding layers may block active sites of 

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