Investigations of gold(I) complexes as inhibitors of caspase-1

Volume 275, February 2026, 113133

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Gold(I) inhibits caspase-1

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DFT calculations predict gold, not ligand, dictates binding

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Crystal structure solved for two gold phosphite complexes

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Small alkyl and aryl phospine ligands on gold led to potent, low nM inhibition

Abstract

Caspase-1 is a key enzyme in the inflammasome that turns on the inflammation cascade. It has been implicated in a variety of disease conditions, including gout, rheumatoid arthritis and inflammatory diseases. Gold complexes have long been studied for their anti-inflammatory properties. The active site of caspase-1 contains a cysteine thiolate, and given that sulfur is aurophilic, we hypothesized that gold complexes would inhibit caspase-1. In this work, we examined a series of gold(I) molecular species for inhibition of caspase-1. It was found that many of the complexes were effective inhibitors at the nanomolar range, with the most effective being PMe3AuCl (KI = 8 nM) and PPh3AuCl (KI = 9 nM). This highlights the value of gold(I) complexes as drug molecules that target cysteine-dependent proteins for disease states.

Graphical abstractGold(I) complexes containing thiols, alkyl and aryl phosphines, and phosphites as ligands were potent, low nM IC50 inhibitors of caspase-1. Unlabelled Image