Dual-bioorthogonal catalysis by a palladium peptide complex

Artificial metalloenzymes (ArMs) enrich bioorthogonal chemistry with new-to-nature reactions while limiting metal deactivation and toxicity. This enables biomedical applications such as activating therapeutics in situ. However, while combination therapies are becoming widespread anticancer treatments, dual catalysis by ArMs has not yet been shown. We present a heptapeptidic ArM with a novel peptide ligand carrying a methyl salicylate palladium complex. We observed that the peptide scaffold reduces metal toxicity while protecting the metal from deactivation by cellular components. Importantly, the peptide also improves catalysis, suggesting involvement in the catalytic reaction mechanism. Our work shows how a palladium-peptide homogeneous catalyst can simultaneously mediate two types of chemistry to synthesize anticancer drugs in human cells. Methyl salicylate palladium LLEYLKR peptide (2-Pd) succeeded to simultaneously produce paclitaxel by depropargylation, and linifanib by Suzuki-Miyaura cross-coupling in cell culture, thereby achieving combination therapy on non-small-cell lung cancer (NSCLC) A549 cells.