The intrinsic reactivity of [Au(bnpy)Cl2] toward the 12-mer C-terminal peptide of human thioredoxin reductase revealed mechanistic insights into the chemoselective arylation of the Cys-Sec pair of the enzyme. The reductive elimination and liberation of gold(I) is the key step of the process occurring more rapidly at selenocysteine than at cysteine.
ABSTRACT
Thioredoxin reductase (TrxR) is a well-known target for gold-based drugs, which typically behave as strong inhibitors of this selenoenzyme. Despite recent evidence that cyclometalated Au(III) complexes inhibit TrxR1 and arylate cysteine (Cys)- and selenocysteine (Sec)-containing systems, there is still limited direct mechanistic evidence at the level of the TrxR C-terminal motif containing a Cys-Sec pair that is essential for catalytic activity. In this study, we investigated the intrinsic reactivity of a cyclometalated Au(III) compound, namely [Au(bnpy)Cl2], toward the 12-mer C-terminal peptide of human TrxR1, at a molecular level, to gain mechanistic insights into the chemoselective arylation of TrxR1. Time-dependent and reagent-ratio studies showed that reductive elimination and liberation of gold(I) is the key step in the process that occurs more rapidly at selenocysteine than at cysteine. Furthermore, comparable extents of arylation were observed under organic and biocompatible conditions, highlighting the efficiency of this transformation in physiologically relevant media. Overall, these findings provide direct mechanistic support for exploiting cyclometalated gold(III) complexes as covalent, Sec-directed agents for targeting thioredoxin reductase and related redox-active proteins. The TrxR C-terminal peptide offers a minimal but informative model to rationalize how scaffold-dependent reactivity can translate into selective and potent inhibition of the full enzyme.
