Cysteine proteases as targets for metal-based drugs

Abstract

The discovery of the platinum anticancer drug cisplatin provided a major stimulus for research into metal-based drugs. The molecular target for the platinum agents is DNA; however recent developments in inorganic medicinal chemistry have identified several alternative novel targets for metal-based drugs. Biological molecules with essential thiol groups are attractive targets. Thiol-containing molecular targets include the redox enzymes thioredoxin reductase and glutathione reductase, transcription factors, and cysteine proteases such as caspases and cathepsins. Inorganic chemistry offers many opportunities for medicinal chemistry, and alternative targets for metal-based drugs are reviewed, with a focus on cysteine proteases. The cathepsin cysteine proteases have numerous physiological functions, and have been implicated in diseases including cancer, autoimmune and inflammatory, and parasitic diseases. The catalytic mechanism of these enzymes is dependent upon a cysteine at the active site. We postulate that metal complexes can inhibit these enzymes via a ligand substitution with the thiol of the active site cysteine. We have investigated several classes of metal complexes including cyclometalated organo gold(III) and Pd(II) complexes, and a series of rhenium(V) mixed ligand oxorhenium complexes as inhibitors of cathepsin cysteine proteases. Mechanistic studies were conducted on the latter supporting the hypothesis of active site-directed inhibition. These data are reviewed below and discussed in the context of possible therapeutic applications including cancer and parasitic disease.