Gold-containing drugs and the control of proteolytic enzymes

1 NaAuCl4 and aurothioglucose inhibited trypsin in free solution without the need of a carrier molecule. 2 NaAuCl4, aurothioglucose, aurothiomalate, auranofin and chloro-triethyl phosphine) gold all inhibited the trypsin-like neutral protease on the surfaces of Ehrlich ascites tumour cell membranes equally well. 3 Crude cathepsin preparations were activated by low concentrations of dithiothreitol and also by aurothioglucose, due to the displacement of an inhibitor. 4 Thiol-activated cathepsins were inhibited by each of the gold derivatives. The gold could be withdrawn from the enzyme by incremental additions of thiols such as reduced glutathione and cysteine with regeneration of enzymic activity. 5 Lineweaver-Burk plots of kinetic data indicated that gold acted as a non competitive inhibitor of cathepsins. 6 A naturally occurring inhibitor of cathepsins was extracted from cartilage. The mechanism of inhibition was again shown to be a thiol-disulfide exchange, the disulphide being provided by the inhibitor and the thiol being provided by the enzyme. 7 The role of gold in the attempted control of proteolysis in the rheumatoid arthritis is briefly discussed in terms of reversible exchange reactions involving gold thiols, disulphides and cartilage inhibitors of proteolytic enzymes.