Although numerous antisickling agents that chemically bind with sickle hemoglobin (Hb S) and inhibit sickling of sickle erythrocytes (SS cells) in vitro were reported and some of them were brought to clinical trials, none were satisfactory for clinical use. The major problem with this type of drugs is the difficulty of delivering a sufficient amount of antisickling drug to intracellular Hb S because:

  1. chemicals that bind with the side chains of hemoglobin also bind with the side chains of other proteins in the gastrointestinal tract, blood and red blood cells (RBCs) prior to binding with intracellular Hb S; and

  2. the concentration of Hb S in SS cells is very high (5 mM of tetrameric Hb S, 20 mM of Hb subunits, or a total amount of approximately 500 grams of Hb S in an adult patient), and the amount of chemical that reaches SS cells upon oral administration cannot modify a significant portion of Hb S to inhibit sickling of SS cells.

For these reasons, drugs that chemically bind with Hb S including those that form Schiff base adducts with Hb S seem to have no clinical value. We found that certain aromatic aldehydes that bind with Hb S allosterically do not have these problems. Since these compounds combine with Hb S physically like a key-and-lock relationship, a low concentration (such as less than 2 mM) of such compound in the blood can bind with a large portion of intracellular Hb S, shift the oxygen equilibrium curve toward the left and inhibit sickling of SS cells (

Brit. J. Hematol.
128
:
552
–561,
2005
). This type of allosteric binding between aromatic aldehydes and Hb is analogous to the binding between 2,3-diphosphoglycerate and Hb. Quite interestingly, our investigations indicate that NIPRISAN (NICOSAN), an herbal medicine that shows a strong antisickling effect both in vitro and in vivo (in transgenic sickle mice) (
Brit. J. Haematol.
118
:
337
–343,
2002
;
Brit. J. Haematol.
122
:
1001
–1008
2003
), contains various aromatic aldehydes (unpublished data). Allosteric drugs designed to interact with specific proteins in the body may be useful as a new type of therapeutic modality for the treatment of sickle cell disease and other diseases. [Researchers with candidate drugs that may have beneficial effects for SCD are welcome to contact the SCD Reference Laboratory for free in vitro evaluation of their agents (for more information, please see our website at www.tatcom.com/sickle-cell).

Disclosure: No relevant conflicts of interest to declare.

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