Premium
CO‐MP4, a polyethylene glycol‐conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats
Author(s) -
Vandegriff K D,
Young M A,
Lohman J,
Bellelli A,
Samaja M,
Malavalli A,
Winslow R M
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.219
Subject(s) - chemistry , pegylation , polyethylene glycol , hemoglobin , carbon monoxide , oxygen , peg ratio , stereochemistry , biochemistry , organic chemistry , finance , economics , catalysis
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 (O 2 /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 β chains in MP4, with α 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. British Journal of Pharmacology (2008) 154 , 1649–1661; doi: 10.1038/bjp.2008.219 ; published online 9 June 2008