Cisplatin Analogs Confer Protection against Cyanide Poisoning

Highlights

• Cyanide antidotes discovered by structure-activity relationships of cisplatin

• Sulfur-containing ligands are a key feature of platinum-based cyanide antidotes

• Cisplatin analogs act as antidotes by binding up to five cyanide anions

• Antidote activity is conserved in zebrafish, mice, and rabbits

Summary

Cisplatin holds an illustrious position in the history of chemistry most notably for its role in the virtual cure of testicular cancer. Here we describe a role for this small molecule in cyanide detoxification in vivo. Cyanide kills organisms as diverse as insects, fish, and humans within seconds to hours. Current antidotes exhibit limited efficacy and are not amenable to mass distribution requiring the development of new classes of antidotes. The binding affinity of the cyanide anion for the positively charged metal platinum is known to create an extremely stable complex in vitro. We therefore screened a panel of diverse cisplatin analogs and identified compounds that conferred protection from cyanide poisoning in zebrafish, mice, and rabbits. Cumulatively, this discovery pipeline begins to establish the characteristics of platinum ligands that influence their solubility, toxicity, and efficacy, and provides proof of concept that platinum-based complexes are effective antidotes for cyanide poisoning.