Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation

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14 Scopus citations


Transition-metal-based approaches to selectively modify proteins hold promise in addressing challenges in chemical biology. Unique bioorthogonal chemistry can be achieved with preformed metal-based compounds; however, their utility in native protein sites within cells remain underdeveloped. Here, we tune the ancillary ligands of cyclometalated gold(III) as a reactive group, and the gold scaffold allows for rapid modification of a desired cysteine residue proximal to the ligand binding site of a target protein. Moreover, evidence for a ligand association mechanism toward C-S bond formation by X-crystallography is established. The observed reactivity of cyclometalated gold(III) enables the rational design of a cysteine-targeted covalent inhibitor of mutant KRAS. This work illustrates the potential of structure-activity relationship studies to tune kinetics of cysteine arylation and rational design of metal-mediated ligand affinity chemistry (MLAC) of native proteins.

Original languageEnglish
Pages (from-to)14582-14593
Number of pages12
JournalInorganic Chemistry
Issue number19
StatePublished - Oct 4 2021

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ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Inorganic Chemistry


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