In:
Blood Advances, American Society of Hematology, Vol. 3, No. 9 ( 2019-05-14), p. 1493-1498
Abstract:
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 γ1/γ2 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.
Type of Medium:
Online Resource
ISSN:
2473-9529
,
2473-9537
DOI:
10.1182/bloodadvances.2019031120
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2019
detail.hit.zdb_id:
2876449-3
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