Preparation of poly- <i>N</i> -(methyl)aminooxy serine polypeptides by NCA ring-opening polymerization for modification with reducing oligosaccharides

<i>N</i>-Carboxyanhydride (NCA) ring-opening polymerization offers an attractive approach for the construction of polypeptides. Here, we report the synthesis of a serine NCA-functionalized monomer bearing a methylaminooxy group, enabling post-polymerization attachment of complex oligosaccharides <i>via</i> a neo-glycosylation reaction. It provides an attractive alternative to traditional click reactions, allowing direct conjugation of glycans with a free reducing end without requiring a reactive linker or toxic reagents. Enzymatically produced 6-sialyl lactose was efficiently conjugated to the methylaminooxy moieties of the polypeptide. The resulting neo-glycopolymer was analyzed by size-exclusion chromatography (SEC) to determine molecular weight and by diffusion-ordered spectroscopy (DOSY) nuclear magnetic resonance (NMR), which confirmed a high degree of functionalization and a substantial increase in hydrodynamic radius. Glycan attachment proceeds under mild acidic conditions highlighting the versatility of the polypeptide scaffold to yield brush-like glycosylated polypeptides.