DEVELOPMENT OF ANTIDOTES FOR CARBON MONOXIDE (CO) POISONING

Carbon monoxide (CO) remains the most common cause of poisoning worldwide with no specific antidote available. CO causes systemic ischemia by reducing oxygen delivery and utilization. Using site-directed mutagenesis, we have developed unique hemoglobin-like molecules that exhibit extremely high affinity for CO. These studies suggest that an optimal CO antidote would be administered intravenously and possess several key properties: (a) high CO-binding affinity (KA); (b) high M value, indicating the affinity for CO relative to oxygen (K_CO/K_O2); (c) thermal and chemical stability; (d) low auto-oxidation rates; and (e) low reactivity with nitric oxide (NO). Recently, we have developed a mutationally engineered neuroglobin molecule and a bacterial CO-binding transcription factor called the regulator of carbon monoxide metabolism (RcoM) that bind CO with near-irreversible affinity and show potential as antidotes. These molecules scavenge CO and deliver a molecule of oxygen, suggesting dual roles as CO antidotes and oxygen carriers.