Phthalides serve as potent modulators to boost fetal hemoglobin induction therapy for β-hemoglobinopathies

Wei-Ren Chen, Chia-Cheng Chou and Chia C. Wang

Key Points

  • z-Butylidenephthalide and z-ligustilide act as more potent HbF allosteric modulators than 2,3-BPG in lowering the oxygen affinity of HbF.

  • z-Butylidenephthalide and z-ligustilide aid HbF induction therapy for β-hemoglobinopathies by tuning HbF function closer to that of HbA.


Fetal hemoglobin (HbF) induction therapy has become the most promising strategy for treating β-hemoglobinopathies, including sickle-cell diseases and β-thalassemia. However, subtle but critical structural difference exists between HbF and normal adult hemoglobin (HbA), which inevitably leads to reduced binding of the endogenous modulator 2,3-bisphosphoglycerate (2,3-BPG) to HbF and thus increased oxygen affinity and decreased oxygen transport efficiency of HbF. We combined the oxygen equilibrium experiments, resonance Raman (RR) spectroscopy, and molecular docking modeling, and we discuss 2 phthalides, z-butylidenephthalide and z-ligustilide, that can effectively lower the oxygen affinity of HbF. They adjust it to a level closer to that of HbA and make it a more satisfactory oxygen carrier for adults. From the oxygen equilibrium curve measurements, we show that the 2 phthalides are more effective than 2,3-BPG for modulating HbF. The RR spectra show that phthalides allosterically stabilize the oxygenated HbF in the low oxygen affinity conformation, and the molecular docking modeling reveals that the 2 chosen phthalides interact with HbF via the cleft around the γ12 interface with a binding strength ∼1.6 times stronger than that of 2,3-BPG. We discuss the implications of z-butylidenephthalide and z-ligustilide in boosting the efficacy of HbF induction therapy to mitigate the clinical severities of β-hemoglobinopathies.

  • Submitted January 7, 2019.
  • Accepted March 19, 2019.
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