To meet this need, chemical biology and medicinal chemistry approaches are required to discover lead compounds for development into new classes of antidotes to cyanide poisoning. The large global supply of cyanide, the morbidity and mortality from smoke inhalation and industrial accidents, and the threat to soldiers fighting nonconventional conflicts requires the development of novel classes of antidotes that are amenable to mass distribution in the field. Though there are two available antidotes for cyanide poisoning, their formulation and mode of action require them to be administered intravenously in hospital settings, therefore they would not be amenable to a mass causality scenario such as the Bhopal disaster ( Hall et al., 2009). The Bhopal disaster, considered the world's worst industrial accident, occurred when 45 tons of methyl isocyanate and hydrogen cyanide escaped from reservoirs killing nearly 4,000 people immediately, followed by another 15,000-20,000 individuals over the next few weeks, and leaving a half a million survivors with debilitating injuries such as chronic respiratory illnesses and blindness ( Broughton, 2005). Industrial accidents are another major source of cyanide morbidity and mortality. The thermal breakdown of materials such as wool, plastic, and synthetic polymers produce cyanide gas in addition to isocyanates (potent respiratory irritants), leading to smoke inhalation fatalities of approximately 5,000-10,000 and injuries of 23,000 per year in the United States ( Alcorta, 2004). Manufacturers in the United States produce 300,000 tons of hydrogen cyanide annually which is used in the extraction of gold during mining and in the synthesis of dyes, synthetic fibers, and plastics, as well as in warehouses as a pesticide. If not reversed, the cessation of aerobic metabolism causes a fatal deficit in oxygen consumption. Consequently, electron transport and oxidative phosphorylation are halted. Cyanide reversibly binds to cytochrome c oxidase within the mitochondria ( Kellin, 1929). Smoke inhalation is the most common cause of cyanide poisoning in western countries ( Barillo et al., 1994). Historically, cyanide has been an agent of murder, war and terrorism however unintentional exposures are equally possible and lethal. 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. We therefore screened a panel of diverse cisplatin analogs and identified compounds that conferred protection from cyanide poisoning in zebrafish, mice and rabbits. The binding affinity of the cyanide anion for the positively charged metal platinum is known to create an extremely stable complex in vitro. Current antidotes exhibit limited efficacy and are not amenable to mass distribution requiring the development of new classes of antidotes. Cyanide kills organisms as diverse as insects, fish and humans within seconds to hours. Here we describe a role for this small molecule in cyanide detoxification in vivo. Cisplatin holds an illustrious position in the history of chemistry most notably for its role in the virtual cure of testicular cancer.
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