Streamlined Identification of Metallopeptides for Intracellular Catalysis Using Positionally Addressable Combinatorial Libraries

The discovery and development of artificial catalysts to carry out bioorthogonal reactions in living cells is a primary goal at the interface of Chemistry and Biology. Current approaches rely on time-consuming trial-and-error methods. As an alternative, we show that positionally addressable combinatorial libraries (SPOT libraries) provide a significant advantage for the efficient identification of novel catalytic metallopeptides. Using these libraries, we were able to rapidly identify catalytic β-hairpin palladopeptides capable of promoting efficient depropargylation reactions in challenging intracellular environments.