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Cell Chem Biol. 2017 May 18;24(5):565-575.e4. doi: 10.1016/j.chembiol.2017.03.013. Epub 2017 Apr 13.

Cisplatin Analogs Confer Protection against Cyanide Poisoning.

Author information

1
Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: anjali.nath@aya.yale.edu.
2
Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
3
Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02215, USA.
4
Department of Medicine, Beckman Laser Institute, University of California, Irvine, CA 92697, USA.
5
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
6
Division of Cardiology, Brigham and Women's Hospital, Boston, MA 02115, USA.
7
Broad Institute, Cambridge, MA 02142, USA; Division of Cardiology, Brigham and Women's Hospital, Boston, MA 02115, USA.
8
Broad Institute, Cambridge, MA 02142, USA; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
9
Division of Cardiology, Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA. Electronic address: randall.peterson@pharm.utah.edu.

Abstract

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.

KEYWORDS:

antidote; cisplatin; cyanide; phenotypic screening; platinum; zebrafish

PMID:
28416275
PMCID:
PMC5472353
DOI:
10.1016/j.chembiol.2017.03.013
[Indexed for MEDLINE]
Free PMC Article

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