Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning

Science Translational Medicine  07 Dec 2016:
Vol. 8, Issue 368, pp. 368ra173
DOI: 10.1126/scitranslmed.aah6571

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Antidote for an invisible foe

We cannot see it, taste it, or smell it. Nevertheless, carbon monoxide is a deadly poison; it is a frequent cause of poisoning all over the world. This gaseous product of incomplete combustion displaces the oxygen molecules carried by hemoglobin throughout the body, thereby starving tissues of oxygen and causing death. Now, Azarov et al. have reengineered neuroglobin, a hemoglobin-like protein from the brain, so that it binds carbon monoxide more quickly and tightly than does hemoglobin. When CO-poisoned mice are infused with the artificial neuroglobin, it scavenges the CO, freeing hemoglobin to perform its oxygen delivery duty. The engineered neuroglobin ensures the survival of CO-poisoned mice. The half-life of CO in human red blood cells treated with neuroglobin is only 25 s, compared with a published half-life of 20 min with hyberbaric oxygen, the best treatment currently available. Engineered globins show encouraging promise as antidotes for this lethal gas.


Carbon monoxide (CO) is a leading cause of poisoning deaths worldwide, with no available antidotal therapy. We introduce a potential treatment paradigm for CO poisoning, based on near-irreversible binding of CO by an engineered human neuroglobin (Ngb). Ngb is a six-coordinate hemoprotein, with the heme iron coordinated by two histidine residues. We mutated the distal histidine to glutamine (H64Q) and substituted three surface cysteines with less reactive amino acids to form a five-coordinate heme protein (Ngb-H64Q-CCC). This molecule exhibited an unusually high affinity for gaseous ligands, with a P50 (partial pressure of O2 at which hemoglobin is half-saturated) value for oxygen of 0.015 mmHg. Ngb-H64Q-CCC bound CO about 500 times more strongly than did hemoglobin. Incubation of Ngb-H64Q-CCC with 100% CO-saturated hemoglobin, either cell-free or encapsulated in human red blood cells, reduced the half-life of carboxyhemoglobin to 0.11 and 0.41 min, respectively, from ≥200 min when the hemoglobin or red blood cells were exposed only to air. Infusion of Ngb-H64Q-CCC to CO-poisoned mice enhanced CO removal from red blood cells, restored heart rate and blood pressure, increased survival, and was followed by rapid renal elimination of CO-bound Ngb-H64Q-CCC. Heme-based scavenger molecules with very high CO binding affinity, such as our mutant five-coordinate Ngb, are potential antidotes for CO poisoning by virtue of their ability to bind and eliminate CO.

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