Cisplatin Analogs Confer Protection against Cyanide Poisoning. Issue 5 (18th May 2017)

• Record Type: Journal Article
• Authors: Nath, Anjali K.; Shi, Xu; Harrison, Devin L.; Morningstar, Jordan E.; Mahon, Sari; Chan, Adriano; Sips, Patrick; Lee, Jangwoen; MacRae, Calum A.; Boss, Gerry R.; Brenner, Matthew; Gerszten, Robert E.; Peterson, Randall T.
• Is Part Of: Cell chemical biology. Volume 24:Issue 5(2017)
• Page Start: 565
• Page End: 575.e4
• Publication Date: 2017-05-18
• Subjects: phenotypic screening -- cyanide -- antidote -- cisplatin -- platinum -- zebrafish; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.03.013
• Languages: English
• ISSNs: 2451-9456

Abstract

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. Graphical Abstract: 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 Abstract : Annually, one million new patients receive the chemotherapeutic drug cisplatin. Here Nath et al. provide proof of concept data that cisplatin analogs are antidotes to cyanide poisoning in three vertebrate species and identify a lead compound for further drug development.