Mechanisms, therapeutic uses, and developmental perspectives of redox-active thiomolybdates

Redox-active, copper-chelating thiomolybdates are a family of metal-based therapeutics used to treat copper toxicity in animals and Wilson's disease in humans, and studied in other indications including cancer, inflammatory and fibrotic conditions. Thiomolybdates act through multiple mechanisms including copper chelation, redox regulation (e.g., superoxide dismutase inhibition), and modulation of inflammation. We and others have also identified thiomolybdates as slow-release sulfide donors that inhibit mitochondrial respiration, limit mitochondrial reactive oxygen species (ROS) production, augment antioxidant reserve capacity, and confer organ- and whole-body protection in non-clinical models of reperfusion injury. Here we review the rich history of the thiomolybdate drug class, focusing on their activity across multiple pathologies, utility in non-clinical and clinical settings, accepted and proposed mechanisms of action, developmental perspectives, and limitations. Context-specific use of thiomolybdates support their development as either first-in-class or next generation therapeutics across several disease areas. Dosing and route of administration differentiate the utility of thiomolybdates as either copper chelators (oral administration over several weeks) or sulfide donors (acute intravenous use). Further work is however required to understand the impact of both opposing and additive mechanisms of action. Examples include reduction of ROS generation versus superoxide dismutase inhibition in oxidative pathologies, and the opposing angiogenic effects of copper chelation and sulfide bioavailability in the tumor microenvironment.