Open AccessTuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation
Author(s) -
Sailajah Gukathasan,
Sean Parkin,
Esther P. Black,
Samuel G. Awuah
Publication year - 2021
Publication title -
inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.348
H-Index - 233
eISSN - 1520-510X
pISSN - 0020-1669
DOI - 10.1021/acs.inorgchem.1c01517
Subject(s) - chemistry , bioconjugation , cysteine , ligand (biochemistry) , rational design , bioorthogonal chemistry , covalent bond , combinatorial chemistry , chemical biology , reactivity (psychology) , stereochemistry , residue (chemistry) , nanotechnology , biochemistry , receptor , click chemistry , organic chemistry , enzyme , medicine , materials science , alternative medicine , pathology
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.