SuFEx‐Enabled Polypeptide: Creating Diversified Properties with Minimal Preset Conditions

Abstract Facile but effective synthesis and functionalization of polypeptides has long been a challenge, blocking the way to further explorations of their properties and potential applications. Here, we report the incorporation of sulfur(VI)‐fluoride exchange (SuFEx) moiety in amino acid N‐carboxyanhydrides, which grant the resulting polypeptides from ring‐opening polymerization the ability to utilize simple hydroxyl and amino groups on functional moieties of interest without the requirement for the introduction of preset conditions, such as reactive molecular anchors. We prepared series of polypeptides modified with sulfates or amidosulfonates (sulfamates), and importantly, we demonstrate that such linkages derived from SuFEx exhibit unique nature, which possibly benefits future biomaterial designs. In addition, the linkages can synergize with incorporated functionalizing moieties, demonstrated in a proof‐of‐concept example in which the sulfate‐linked, saccharide‐modified polypeptides showed outstanding antiviral activity and biocompatibility.