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

ABSTRACT: Fetal hemoglobin (HbF) induction therapy has become the most promising strategy for treating ?-hemoglobinopathies, including sickle-cell diseases and ?-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 ?1/?2 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 ?-hemoglobinopathies.

SUBMITTER: Chen WR 

PROVIDER: S-EPMC6517670 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature