Click and release through bioorthogonal hydroamination

Over the last two decades, click and bioorthogonal chemistry have become essential tools for modifying and probing biological systems. Early efforts primarily focused on conjugation reactions that install probes, affinity tags, or small molecules onto biomolecules. In contrast, click-induced dissociation reactions enable the removal of a functional moiety through bond cleavage. While both strategies are widely applied in vitro and in vivo, coordinating multiple interdependent chemical transformations in a controlled and modular manner remains a significant challenge. Here, we describe a click-and-release strategy based on a bioorthogonal hydroamination reaction that generates a discrete, isolable conjugate. These intermediates permit additional chemical or biochemical transformations prior to the independent induction of bond cleavage, enabling greater operational flexibility in a biological context.