Redirecting Intermediary Metabolism to Counteract Cyanide Poisoning

Abstract

Cyanide is one of the oldest known poisons in human history. In the 1980’s, seminal work began to elucidate the toxic cellular mechanisms of cyanide. In the 1990’s, endogenous metabolites were shown to sequester cyanide and these became promising avenues for the development of a cyanide antidote. However, a metabolite-based cyanide antidote did not come to fruition. More recently, in the past 10 years, advances in mass spectrometry-based metabolomics profiling, subcellular targeting, and genome editing have brought fresh perspectives to the concept of a metabolism-based cyanide antidote. Here, we present the theory of redirecting intermediary metabolism to counteract cyanide poisoning. We also present evidence that supports our theory. Importantly, this represents a significant paradigm shift from current treatments which aim to sequester the chemical toxicant but do not mitigate the acute biological sequelae or the more prolonged-term effects of cyanide. This paradigm changes the clinical management of cyanide poisoning and also has implications for the unmet medical needs in challenging emergency settings such as mass casualty chemical exposure incidents.