Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation.
Sailajah GukathasanSean ParkinEsther P BlackSamuel G AwuahPublished in: Inorganic chemistry (2021)
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.
Keyphrases
- transition metal
- fluorescent probe
- living cells
- silver nanoparticles
- structure activity relationship
- induced apoptosis
- amino acid
- protein protein
- cell cycle arrest
- drug discovery
- wild type
- binding protein
- risk assessment
- cancer therapy
- oxidative stress
- climate change
- case control
- signaling pathway
- endoplasmic reticulum stress
- quantum dots