CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats

Br J Pharmacol. 2008 Aug;154(8):1649-61. doi: 10.1038/bjp.2008.219. Epub 2008 Jun 9.


Background and purpose: MP4 (Hemospan) is a Hb-based oxygen therapeutic agent, based on polyethylene-glycol (PEG) conjugation to Hb, undergoing clinical trials as an oxygen carrier. This study describes the functional interaction between MP4 and carbon monoxide (CO), as a CO delivery agent, and the effects of CO-MP4 on myocardial infarct size following ischaemia and reperfusion in rats.

Experimental approach: Kinetic measurements of CO-MP4 binding were used to evaluate the effects of PEG modification on Hb subunit structure/function and to calculate CO-MP4 equilibrium constants. CO transport by CO-MP4 was shown by ligand (O2/CO) partitioning between MP4 and red blood cell (RBC)-Hb. Pharmacological effects of CO-MP4 were studied on myocardial infarction in rats.

Key results: CO binding kinetics show primary structural/functional effects on beta chains in MP4, with alpha chains maintaining the ability to undergo tertiary conformational transition. CO confers long-term, room-temperature stability and is able to rapidly re-equilibrate between MP4 and RBCs. In a rat model of myocardial infarct, in contrast to oxy-MP4, CO-MP4 reduced infarct size when administered prior to the induction of ischaemia.

Conclusions and implications: MP4 PEGylation chemistry modifies the individual function of Hb subunits, but results in an overall CO equilibrium constant similar to that for unmodified Hb. CO-MP4 is able to deliver CO to the circulation and reduces ischaemia/reperfusion injury in rats, providing the first evidence for this drug as a CO therapeutic agent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Monoxide / administration & dosage
  • Carbon Monoxide / chemistry
  • Carbon Monoxide / pharmacology*
  • Disease Models, Animal
  • Drug Stability
  • Erythrocytes / metabolism
  • Hemoglobins / administration & dosage
  • Hemoglobins / chemistry
  • Hemoglobins / pharmacology*
  • Male
  • Maleimides / administration & dosage
  • Maleimides / chemistry
  • Maleimides / pharmacology*
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacology*
  • Rats
  • Rats, Sprague-Dawley


  • Hemoglobins
  • Maleimides
  • maleimide-polyethylene glycol-modified hemoglobin, MP4
  • Polyethylene Glycols
  • Carbon Monoxide