Carbohydrate PEGylation, an approach to improve pharmacological potency

Abstract

Conjugation with polyethylene glycol (PEG), known as PEGylation, has been widely used to improve the bioavailability of proteins and low molecular weight drugs. The covalent conjugation of PEG to the carbohydrate moiety of a protein has been mainly used to enhance the pharmacokinetic properties of the attached protein while yielding a more defined product. Thus, glycoPEGylation was successfully applied to the introduction of a PEGylated sialic acid to a preexisting or enzymatically linked glycan in a protein. Carbohydrates are now recognized as playing an important role in host-pathogen interactions in protozoal, bacterial and viral infections and are consequently candidates for chemotherapy. The short in vivo half-life of low molecular weight glycans hampered their use but methods for the covalent attachment of PEG have been less exploited. In this review, information on the preparation and application of PEG-carbohydrates, in particular multiarm PEGylation, is presented.

Keywords: bioavailability; carbohydrates; conjugates; glycoPEGylation; multivalent PEGylation; multivalent glycosystems.

Figure 1

Types of PEG utilized for derivatization of drugs and peptides.

Figure 2

Activated PEG derivatives for conjugation.

Scheme 1

Chemoenzymatic method for the preparation of PEG-CMP-SA, adapted from [–33].

Scheme 2

GlycoPEGylation by sequential in vitro, enzyme mediated, O-glycosylation followed by transfer of PEGylated sialic acid, adapted from [31].

Scheme 3

Chemical glycation of a protein and PEGylation after periodate oxidation, adapted from [34].

Scheme 4

PEGylation of native glycosylated proteins after modification of the glycan. (A) Enzymatic modification of the glycan; (B) Chemical modification of the glycan, adapted from [38].

Scheme 5

PEGylation of a pentofuranose derivative, adapted from [41].

Scheme 6

Galactosyl PEGylation of polystyrene nanoparticles, adapted from [42].

Figure 3

Mannosyl PEGylated polyethylenimine for delivery systems. (A) Mannose and PEG are independently linked to the PEI backbone; (B) Mannose is attached to PEI via a PEG chain, adapted from [44].

Figure 4

PEGylated mannose derivatives, adapted from [45].

Scheme 7

PEGylation of lactose analogs [53].

Scheme 8

Conjugation of lactose analogs with dendritic PEGs [54].

Figure 5

PEGylated chitosan derivative, adapted from [61].

Figure 6

Chitosan/PEG functionalized with a mannose at the distal end, adapted from [62].