Oxygen therapeutics: can we tame haemoglobin?

The need for blood transfusions in wartime and the emerging threat of infection from blood and blood products have motivated several commercial companies to develop compounds that aim to substitute for the oxygen-transport function of blood.At present, there are two classes of such 'blood substitutes' under active development: haemoglobin-based oxygen carriers (HBOCs) and fluorocarbon-based oxygen carriers (FBOCs). As the most widely explored approach for the development of blood substitutes has been the adaptation of haemoglobin (Hb), this review focuses on HBOCs.Hb in adult red-blood cells (RBCs) is a tetramer of two α and two β polypeptide chains. An iron-containing haem prosthetic group is buried in a hydrophobic pocket in each chain and is capable of carrying one oxygen molecule per haem.A variety of HBOCs with chemical or genetic modifications that are intended to stabilize Hb outside its natural environment — red blood cells (RBCs) — in a functional tetrameric and/or polymeric form have been developed.However, because of the initial success in manufacturing, and preclinical and clinical testing in normal healthy volunteers, little attention was paid to the inner working of the Hb molecule, or to the effects of chemical and/or genetic modifications on the integrity and stability of the protein.There have now been several well-publicized setbacks in clinical trials of HBOCs. Hb outside its natural protective environment (that is, RBCs) is toxic owing to the fact that Hb is a redox-active molecule. Central to this activity is the haem group — it undergoes redox transition to higher oxidation states with increasing redox reactivity towards biological molecules, leading to tissue toxicity.Chemical and/or genetic modifications of Hb can suppress or enhance these reactions. So, one can design against these reactions by restricting the haem reactivity with biological molecules. Exploring endogenous protective mechanisms and/or inclusion of antioxidants in Hb solutions might also provide some protection against Hb oxidative toxicities.