González González, CarmenMartínez Castro, LauraLearte Aymamí, SorayaPose Insua, ClaraCouceiro, José R.Martin-Malpartida, PauMacias, Maria J.Maréchal, Jean-DidierMascareñas Cid, José LuisVázquez Sentís, Marco Eugenio2025-05-282025-05-282025-05-08ACS Catal. 2025, 15, 10, 8624–8632https://hdl.handle.net/10347/41855This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright © 2025 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acscatal.5c00525The 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.engCatalysisPeptidesCombinatorial chemistryComputational chemistryBiocatalysisjournal article10.1021/acscatal.5c005252155-5435embargoed access