1 research outputs found
A Triazole Disulfide Compound Increases the Affinity of Hemoglobin for Oxygen and Reduces the Sickling of Human Sickle Cells
Sickle cell disease is an inherited
disorder of hemoglobin (Hb).
During a sickle cell crisis, deoxygenated sickle hemoglobin (deoxyHbS)
polymerizes to form fibers in red blood cells (RBCs), causing the
cells to adopt “sickled” shapes. Using small molecules
to increase the affinity of Hb for oxygen is a potential approach
to treating sickle cell disease, because oxygenated Hb interferes
with the polymerization of deoxyHbS. We have identified a triazole
disulfide compound (4,4′-di(1,2,3-triazolyl)disulfide, designated
TD-3), which increases the affinity of Hb for oxygen. The crystal
structures of carboxy- and deoxy-forms of human adult Hb (HbA), each
complexed with TD-3, revealed that one molecule of the monomeric thiol
form of TD-3 (5-mercapto-1H-1,2,3-triazole, designated MT-3) forms
a disulfide bond with β-Cys93, which inhibits the salt-bridge
formation between β-Asp94 and β-His146. This inhibition
of salt bridge formation stabilizes the R-state and destabilizes the
T-state of Hb, resulting in reduced magnitude of the Bohr effect and
increased affinity of Hb for oxygen. Intravenous administration of
TD-3 (100 mg/kg) to C57BL/6 mice increased the affinity of murine
Hb for oxygen, and the mice did not appear to be adversely affected
by the drug. TD-3 reduced in vitro hypoxia-induced sickling of human
sickle RBCs. The percentage of sickled RBCs and the <i>P</i><sub>50</sub> of human SS RBCs by TD-3 were inversely correlated
with the fraction of Hb modified by TD-3. Our study shows that TD-3,
and possibly other triazole disulfide compounds that bind to Hb β-Cys93,
may provide new treatment options for patients with sickle cell disease