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  • Review Article
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Oxygen therapeutics: can we tame haemoglobin?

Nature Reviews Drug Discovery volume 3, pages 152–159 (2004)Cite this article

Key Points

  • 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.

Abstract

Chemically modified or genetically engineered haemoglobins (Hbs) developed as oxygen therapeutics (often termed 'blood substitutes') are designed to correct oxygen deficit due to ischaemia in a variety of clinical settings. These modifications are intended to stabilize Hb outside its natural environment — red blood cells — in a functional tetrameric and/or polymeric form. Uncontrolled haem-mediated oxidative reactions of cell-free Hb and its reactions with various oxidant/antioxidant and cell signalling systems have emerged as an important pathway of toxicity. Current protective strategies designed to produce safe Hb-based products are focused on controlling or suppressing the 'radical' nature of Hb while retaining its oxygen-carrying function.

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Figure 1: The haemoglobin molecule.
Figure 2: Uncontrolled autoxidation of haemoglobin leads to changes in haem geometry and subsequent degradation.
Figure 3: Cell-free haemoglobin consumes NO and creates an oxidative milieu in the vasculature.
Figure 4: Structure of the active site of haemoglobin.

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Acknowledgements

J. S. Olson of Rice University, USA, kindly provided Figures 1 and 4. J. M. Rifkind of the National Institutes of Health, USA, kindly provided the concept for Figure 2.

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The opinions and assertions contained herein are the scientific views of the author and are not to be construed as policy of the United States Food and Drug Administration.

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  1. Division of Hematology, Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, 8800 Rockville Pike, National Institutes of Health Building 29, Room 112, Bethesda, 20892, Maryland, USA

    Abdu I. Alayash

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FURTHER INFORMATION

Center for Biologics Evaluation and Research

Encyclopedia of Life Sciences

Haem structure and function

myoglobin

Glossary

BLOOD SUBSTITUTE

The terms 'blood substitute' and 'artificial blood' are misnomers, as the compounds discussed in this article provide oxygen transport and volume replacement, but do not perform other functions of blood, such as facilitating immune responses, coagulation and transport of nutrients. These agents are more appropriately termed 'haemoglobin-based oxygen carriers' (HBOCs) or 'oxygen therapeutics'.

ELECTRON PARAMAGNETIC RESONANCE

Resonant absorption of microwave radiation by paramagnetic ions or molecules, with at least one unpaired electron spin, and in the presence of static magnetic field.

ENDOTHELIN

A vasoactive peptide produced by endothelium.

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Alayash, A. Oxygen therapeutics: can we tame haemoglobin?. Nat Rev Drug Discov 3, 152–159 (2004). https://doi.org/10.1038/nrd1307

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