Recent advances in the precision synthesis of homogeneous N-linked glycoproteins: Synthetic strategies and discovery of latent functions.

Protein glycosylation crucially regulates the function and stability of mammalian membrane and secreted proteins. However, because biological glycan processing is inherently a non-template-driven process, natural glycoproteins exist as heterogeneous mixtures. This structural heterogeneity has historically hindered the precise study of specific glycoforms. To overcome this fundamental limitation, advanced chemical and semi-synthetic strategies have emerged, now enabling the precise construction of structurally homogeneous glycoproteins. In this review, we highlight recent progress in the chemical and semi-synthetic assembly of these pure glycoforms, with a focus on advanced peptide ligation technologies. Ultimately, by securing scalable access to well-defined synthetic models, these precision techniques are uncovering latent physiological functions and laying the groundwork for novel, highly targeted therapeutics.