Effects of Glycan Density on the Self‐Assembly Behavior of Glycopeptides Prepared via Alternating Polymerization

Abstract

Glycans on glycopeptides play essential roles in regulating the structures, hydration, intermolecular interactions, self‐assembly, and biological functions. Although synthetic glycopeptides have attracted considerable attention as functional self‐assembling materials, the preparation of structurally diverse glycopeptides with precisely controlled glycan densities remains challenging. Herein, we report a versatile synthetic platform for glycopeptides by combining three‐component polymerization with copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC). Polymerization using propargylamine as one of the reaction components affords an alternating peptide bearing terminal alkyne groups, which readily reacts with azide‐functionalized glycans under CuAAC conditions. The resulting glycopeptides spontaneously self‐assemble into micelles in aqueous media, and their self‐assembly behavior strongly depends on glycan density. The glycopeptide bearing a higher glycan density forms kinetically stabilized primary micelles, thereby delaying the formation of secondary aggregates upon cooling, whereas the glycopeptide with a lower glycan density undergoes further aggregation. This stabilization may be attributed to the densely displayed glycan moieties on the micellar surface, which can modulate intermicellar interactions. These findings demonstrate that glycan density serves as a key molecular design parameter for controlling the self‐assembly and stability of glycopeptides, providing a useful guideline for the development of functional glycopeptide‐based supramolecular materials.