TY - JOUR
T1 - Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation
AU - Gukathasan, Sailajah
AU - Parkin, Sean
AU - Black, Esther P.
AU - Awuah, Samuel G.
N1 - Publisher Copyright:
©
PY - 2021/10/4
Y1 - 2021/10/4
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.inorgchem.1c01517
DO - 10.1021/acs.inorgchem.1c01517
M3 - Article
C2 - 34402302
AN - SCOPUS:85114100338
SN - 0020-1669
VL - 60
SP - 14582
EP - 14593
JO - Inorganic Chemistry
JF - Inorganic Chemistry
IS - 19
ER -