Chemical Strategies for Controlling Sulfation in Biomacromolecules

Sulfation is a fundamental post-translational modification that imparts negative charge and structural complexity to biomolecules, thereby regulating molecular recognition, signaling, and homeostasis across all domains of life. Yet, the ability to interrogate the biological functions of sulfation has long been hindered by the difficulty of constructing molecules with defined sulfation patterns. This Account summarizes our efforts to develop chemical strategies that enable precise control over sulfation in glycans and proteins. We describe an organobase-promoted sulfur(VI) fluoride exchange (SuFEx) chemistry that allows early stage, chemoselective <i>O</i>-sulfation across a broad substrate scope, providing a general solution to sulfate installation in complex settings. Building on this foundation, we introduce an iterative "clickable disaccharide" platform for the programmable assembly of sequence-defined heparan sulfate glycomimetics, enabling systematic dissection of sulfation-dependent glycan-protein interactions. Extending these concepts to the protein realm, we developed a fluorosulfate tyrosine strategy that installs latent sulfates into peptides and proteins, which can be unmasked under physiological conditions or light control via hydroxamic-acid-mediated Lossen rearrangement, offering spatiotemporal control of sulfation in living systems. Collectively, these approaches delineate a unified chemical framework for constructing and manipulating sulfated biomacromolecules with molecular precision, opening new opportunities to elucidate and engineer the biological roles of sulfation.