Recent Developments in High-Affinity CO Scavengers as Potential Therapeutics for CO Poisoning

Carbon monoxide (CO) poisoning is the leading cause of non-drug-related poisoning in humans, resulting in an estimated 50,000-100,000 emergency room visits and 1,500-2,000 deaths annually in the United States alone.¹ Current treatment options are limited to oxygen administration via normobaric oxygen therapy (NBOT) or hyperbaric oxygen therapy (HBOT), but no point-of-care antidote is available.¹ This talk will focus on recent developments in high affinity CO scavengers that exploit the uniquely strong CO-heme interaction to selectively bind and sequester CO in preclinical models. These scavengers include engineered human hemoproteins (e.g., neuroglobin⁾², bacterial transcription factors (e.g., RcoM, Regulator of CO Metabolism)³, and bioinspired, water-soluble synthetic Fe-porphyrin complexes.^4-5 These systems demonstrate exceptionally high CO-binding affinities and have shown promising preclinical results in accelerating CO clearance and improving outcomes in acute CO poisoning. Presented will be design principles, synthetic strategies, spectroscopic characterization, and both in vitro and in vivo studies of these CO scavengers, highlighting their therapeutic potential.

References

(1) Rose, J. J.; Wang, L.; Xu, Q.; McTiernan, C. F.; Shiva, S.; Tejero, J.; Gladwin, M. T. Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy. American Journal of Respiratory and Critical Care Medicine 2017, 195 (5), 596-606. DOI: 10.1164/rccm.201606-1275CI.

(2) Azarov, I.; Wang, L.; Rose, J. J.; Xu, Q.; Huang, X. N.; Belanger, A.; Wang, Y.; Guo, L.; Liu, C.; Ucer, K. B.; McTiernan, C. F.; O’Donnell, C. P.; Shiva, S.; Tejero, J.; Kim-Shapiro, D. B.; Gladwin, M. T. Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning. Science Translational Medicine 2016, 8 (368), 368ra173-368ra173. DOI: doi:10.1126/scitranslmed.aah6571.

(3) Dent, M. R.; DeMartino, A. W.; Xu, Q.; Chen, X.; Gandhi, A.; Hwang, H. S.; Bocian, K. A.; Correnti, J. E.; Abdelghany, Y.; Alipour, E.; Ucer, K. B.; Baker, S. R.; Srimath Kandada, A. R.; Bulbul, A.; Kim-Shapiro, D. B.; Rose, J. J.; Tejero, J.; Gladwin, M. T. Engineering a highly selective, hemoprotein-based scavenger as a carbon monoxide poisoning antidote with no hypertensive effect. Proceedings of the National Academy of Sciences 2025, 122 (32), e2501389122. DOI: doi:10.1073/pnas.2501389122.

(4) Droege, D. G.; Johnstone, T. C. A water-soluble iron-porphyrin complex capable of rescuing CO-poisoned red blood cells. Chemical Communications 2022, 58 (16), 2722-2725, 10.1039/D1CC05542A. DOI: 10.1039/D1CC05542A.

(5) Mao, Q.; Kawaguchi, A. T.; Mizobata, S.; Motterlini, R.; Foresti, R.; Kitagishi, H. Sensitive quantification of carbon monoxide in vivo reveals a protective role of circulating hemoglobin in CO intoxication. Communications Biology 2021, 4 (1), 425. DOI: 10.1038/s42003-021-01880-1.