Pegylation and Its Impact on the Design of New Protein-Based Medicines

Abstract

PEGylation is the covalent conjugation of PEG to therapeutic molecules. Protein PEGylation is a clinically proven approach for extending the circulation half-life and reducing the immunogenicity of protein therapeutics. Most clinically used PEGylated proteins are heterogeneous mixtures of PEG positional isomers conjugated to different residues on the protein main chain. Current research is focused to reduce product heterogeneity and to preserve bioactivity. Recent advances and possible future directions in PEGylation are described in this review. So far protein PEGylation has yielded more than 10 marketed products and in view of the lack of equally successful alternatives to extend the circulation half-life of proteins, PEGylation will still play a major role in drug delivery for many years to come.

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

“…Recoveries of partially protected (disubstituted) derivatives were assumed to be the same as those of the corresponding fully substituted prodrug. Knowledge of these ratios allowed us to determine the unknown amount of analyte in a blood sample by measuring the internal standard recovered [54], and using the same calibration curve of resveratrol, since derivatives have the same absorption coefficient of resveratrol itself (y = 5.3085x, where y is the concentration of analyte and x is the integrated area of the HPLC-UV peak).…”

“…Poly(ethylene glycol) chains are a strong candidate: their presence can increase aqueous solubility of hydrophobic drugs, prolong circulation time, slow down hydrolysis, and increase stability in the gastrointestinal tract [48][49][50][51][52][53]. This type of decoration is particularly valuable for protein/polypeptide drugs and drug-carrying liposomes (rev.s, e.g., [54][55][56][57][58][59]), which can be protected from phagocytosis and are less at risk of provoking an immune response. In general, polymer chains with MW in the range of a few to many kDa are employed for these modifications, as they perform better vis-à-vis hydration and immunogenicity.…”

Bioconjugation of therapeutic proteins and enzymes using the expanded set of genetically encoded amino acids

“…More significant impairment was observed when granulocyte colonystimulating factor and growth hormone were modified by amine-reactive PEGs (Bowen et al, 1999;Clark et al, 1996). In addition to reduced activity, heterogeneity of PEGylated proteins arising from numerous positional isomers creates challenges for both structural and functional characterization, hampering the systematic design of a PEGylated protein and its broader application (Ginn et al, 2014;Wang et al, 2002). Positional control of PEGylation through site-specific NNAA incorporation followed by a bioorthogonal reaction was first demonstrated by Schultz and coworkers (Deiters et al, 2004).…”

Emerging Therapeutic Delivery Capabilities and Challenges Utilizing Enzyme/Protein Packaged Bacterial Vesicles

“…Polymers are also utilized to modify proteins and nanoparticle surfaces to improve in vivo stability. The addition of a single or multiple polyethylene glycol chains, also known as pegylation, to therapeutic proteins has become common practice and is used to improve circulation times by reducing host recognition of the foreign proteins [22]. This relatively simple technique can be utilized to tune half life effectively reducing the necessary dosing frequency needed to maintain t herapeutic efficacy [29].…”

“…Polymeric nanoparticles can be further split into three primary categories of crosslinked or biodegradable polymers and pegylated proteins [21][22][23]. Both crosslinked and biodegradable polymeric nanoparticles can be synthesized through a variety of methods that include polymerization reactions, emulsification, nanoprecipitation or solvent evaporation [24].…”