Live‐Cell‐Templated Dynamic Combinatorial Chemistry

Dynamic covalent chemistry combines in a single step the screening and synthesis of ligands for biomolecular recognition. In order to do that, a chemical entity is used as template within a dynamic combinatorial library of interconverting species, so that the stronger binders are amplified due to the efficient interaction with the target. Here we employed whole A549 living cells as template in a dynamic mixture of imines, for which amplification reflects the efficient and selective interaction with the corresponding extracellular matrix. The amplified polyamine showed strong interaction with the A549 extracellular matrix in on‐cell NMR experiments, while combination of NMR, SPR, and molecular dynamics simulations in model systems provided insights on the molecular recognition event. Notably, our work pioneers the use of whole living cells in dynamic combinatorial chemistry, which paves the way towards the discovery of new bioactive molecules in a more biorelevant environment. Whole living cells were used as the template in a dynamic combinatorial chemistry system. The amplified member of the dynamic library showed strong and selective binding to the main glycosaminoglycan of the extracellular matrix of the corresponding cell. This work demonstrates the power of dynamic covalent screening in chemical biology, even in highly challenging biorelevant media.