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1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
2 CNR Institute of Molecular Biology, Pathology and Department of Biochemical Sciences, University of La Sapienza, Rome, Italy
3 Department of Chemistry, Temple University, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: cfrontic{at}jhmi.edu.
With the objective of developing a recombinant oxygen carrier suitable for therapeutic applications, we have employed an Escherichia coli expression system to synthesize in high yield Hb Minotaur,containing 
-human and 
-bovine chains. Polymerization of Hb Minotaur through S-S intermolecular crosslinking was obtained by introducing a Cys at position 9 and substituting the naturally occurring Cys. This homogeneous polymer, Hb Polytaur, has a MW of ~ 500KDa and was resistant toward reducing agents present in blood. In mice the circulating half-time (3h) was five-fold greater than HbA. The half-time of autoxidation measured in blood (46h) exceeded the circulating retention time. Hypervolemic exchange transfusion resulted in increased arterial blood pressure similar to that with albumin. The increase in pressure was less than that obtained by transfusion of cross-linked tetrameric Hb known to undergo renovascular extravasation. The NO reactivity of Hb Polytaur was similar to HbA, indicating that the diminished pressor response to Hb Polytaur was probably related to diminished extravasation. Transfusion of 3% Hb Polytaur during focal cerebral ischemia reduced infarct volume by 22%. Therefore, site-specific Cys insertion on the Hb surface results in uniform size polymers that do not produce a large pressor response indicative of vasoconstriction. Polymerization maintains physiologically relevant oxygen and heme affinity, stability toward denaturation and oxidation, and effective oxygen delivery as indicated by reduced cerebral ischemic damage.
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