Decoding Protein Glycosylation for Better Vaccine and Antibody Development

ConspectusGlycosylation is an important biological process for modulating the structure and function of proteins, cells, and many other biologics. Decoding protein glycosylation and glycan-receptor interactions will help us understand the role of post-translational glycosylation with molecular precision and provide new opportunities for developing better glycoprotein medicines to ameliorate diseases associated with aberrant glycosylation. Over the years, we have developed new tools and methods, notably the chemoenzymatic and programmable one-pot methods, for making and studying complex glycans and glycoproteins and investigating the impact of glycosylation on protein folding, viral infection, cancer progression, and immune responses. This Account highlights the advanced glycosylation methods developed in our laboratory to drive new discoveries in glycobiology and accelerate the translation of these discoveries into innovative development. Representative examples include practical and expedient synthesis of oligosaccharides and glycoproteins, development of glycan microarrays, low-sugar universal vaccines with broadly protective immune responses, cell-based production of monoclonal antibodies with humanized Fc-glycosylation optimized to improve efficacy, and common small-molecule blockades targeting multiple Siglec-mediated immune checkpoints. It is anticipated that advances in glycosylation methodology and the extensive data generated over the years, combined with AI-assisted prediction, will lead to a paradigm change in vaccine and antibody development as well as drug discoveries for human health.