Mapping the glycosylation code through synthetic chemistry

Glycosylation, the most abundant and complex post-translational modification of proteins in extracellular environments—particularly on secreted and membrane-bound proteins—plays critical but still poorly understood roles in modulating protein properties. Although diverse approaches have revealed beneficial effects of glycosylation on many protein characteristics, these effects are often modest, making glycosylation appear less attractive as a general strategy for biotherapeutic development. The concept of a "glycosylation code" is therefore highly compelling. This code is hypothesized to be analogous to the genetic code, in which specific glycosylation patterns are precisely aligned with particular proteins, producing disproportionately strong effects on their properties. This perspective outlines why and how synthetic chemistry offers unique capabilities for mapping the glycosylation code, highlights key future directions required to expand and deepen our understanding, and considers how such insights can be harnessed to realize the full potential of glycosylation in advancing biotherapeutic development.