Chemistry to Explore and Exploit Multivalent Protein–Carbohydrate Interactions

e position of carbohydrates on the cell surface renders them uniquely poised to engage with proteins on the surfaces of other cells or pathogens. Indeed, protein–carbohydrate interactions have been implicated in physiological processes ranging from fertilization to development to immune system function. Given these important functions, it seems surprising that individual protein-carbohydrate interactions are so weak: Their association constants are typically 1000- to 1,000,000-fold poorer than those of protein–protein interactions. To compensate for their low affinity, most protein–carbohydrate interactions are multivalent. Multivalent interactions occur when multiple binding groups (e.g., carbohydrates) on one cell bind to multiple copies of a receptor (e.g., a protein) on another cell. By combining energetic contributions of multiple individual complexes, multivalent interactions are kinetically labile yet exhibit high apparent affinity. These attributes of multivalent interactions complicate the study of protein–carbohydrate interactions. It is challenging to determine if a protein–carbohydrate interaction is relevant, to assess the molecular mechanisms that contribute to formation and stabilization of protein–carbohydrate complexes, and to design potent inhibitors of protein–carbohydrate interactions. To address all of these issues, we developed novel and general synthetic routes to multivalent carbohydrate displays.