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Sci Transl Med. 2016 Dec 7;8(368):368ra173.

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

Author information

1
Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
2
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
3
Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA.
4
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
5
Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
6
Translational Science Center, Wake Forest University, Winston-Salem, NC 27109, USA.
7
Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA. gladwinmt@upmc.edu.

Abstract

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.

PMID:
27928027
PMCID:
PMC5206801
DOI:
10.1126/scitranslmed.aah6571
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

M.T.G. and J.T. have submitted a provisional patent filing on the use of recombinant neuroglobin mutants for carbon monoxide poisoning. The other authors declare that they have no competing interests. Data and Materials Availability: Raw data and materials are available from the authors for noncommercial researchers via a materials transfer agreement.

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