Chemical and Chemoenzymatic Synthesis of Peptide and Protein Therapeutics Conjugated with Human N‐Glycans

Abstract Glycosylation is one of the most ubiquitous post‐translational modifications. It affects the structure and function of peptides/proteins and consequently has a significant impact on various biological events. However, the structural complexity and heterogeneity of glycopeptides/proteins caused by the diversity of glycan structures and glycosylation sites complicates the detailed elucidation of glycan function and hampers their clinical applications. To address these challenges, chemical and/or enzyme‐assisted synthesis methods have been developed to realize glycopeptides/proteins with well‐defined glycan morphologies. In particular, N ‐glycans are expected to be useful for improving the solubility, in vivo half‐life and aggregation of bioactive peptides/proteins that have had limited clinical applications so far due to their short duration of action in the blood and unsuitable physicochemical properties. Chemical glycosylation performed in a post‐synthetic procedure can be used to facilitate the development of glycopeptide/protein analogues or mimetics that are superior to the original molecules in terms of physicochemical and pharmacokinetic properties. N ‐glycans are used to modify targets because they are highly biodegradable and biocompatible and have structures that already exist in the human body. On the practical side, from a quality control perspective, close attention should be paid to their structural homogeneity when they are to be applied to pharmaceuticals.