Dual-bioorthogonal catalysis by a palladium peptide complex

Ana M. Pérez-López, Adam Belsom, Linus Fiedler, Xiaoyi Xin, Juri Rappsilber*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)3301-3311
Number of pages11
JournalJournal of Medicinal Chemistry
Volume66
Issue number5
Early online date23 Feb 2023
DOIs
Publication statusPublished - 9 Mar 2023

Keywords / Materials (for Non-textual outputs)

  • catalysts
  • organic polymers
  • palladium
  • peptides and proteins
  • pharmaceuticals

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