Hemoglobin allostery and pharmacology

The oxygen demands of the human body require the constant circulation of blood carrying an enormous concentration of hemoglobin (Hb). Oxygen transport depends not only on the amount of Hb, but also on the control over the affinity of the protein for the gas, which can be optimized for the environmental conditions by changes in the concentration of effectors (hydrogen ions, chloride, CO2, and DPG) inside the red cell. Some pathological conditions affecting Hb may benefit from pharmacological interventions to increase or decrease its affinity for oxygen, or otherwise modify its properties, or alter its biosynthesis. Examples of such conditions include sickle cell anemia, thalassemias and inherited hemoglobinopathies. Effective and safe drugs such as voxelotor, bezafibrate and efaproxiral are available that significantly increase or decrease Hb oxygen affinity. Some medical conditions not directly affecting the blood or its oxygen carrying capacity may also be relieved by the manipulation of Hb. For example, the standard treatment of acute cyanide poisoning requires the oxidation of a fraction of the Hb in the bloodstream so that it efficiently scavenges cyanide. Tumors are often extremely hypoxic and therefore strongly resistant to radiotherapy; the sensitivity of cancerous tissue to X-rays may be increased by improved oxygenation through drugs binding Hb. This review attempts to provide a systematic exploration of the pharmacology of Hb, its molecular basis, and its intended and possible uses.