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

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.

Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives

“…Oxygen (O 2 ) is essential for life [ 1 ] and physiological processes such as cell growth, differentiation, metabolism, and tissue homeostasis [ 2 , 3 ]. Factors such as trauma [ 4 ], blood loss [ 5 ], pernicious anemia [ 6 ] and ischemic cerebrovascular disease [ 7 , 8 ] can decrease tissue oxygen content, lead to hypoxia [ 9 ]. This, in turn, can induce organ dysfunction, particularly in the brain [ 10 ], heart [ 11 ] and kidney [ 12 ] and leading to irreversible damage and/ or death [ 13 ].…”

Research progress on the pharmacological activities of senkyunolides

“…The bioactive ingredients of L. striatum can be divided into four categories: phenols and organic acids (such as ferulic acid), phthalides (such as ligustilide and senkyunolide), alkaloids (such as ligustrazine), and polysaccharides [2] . Recent pharmacological studies have suggested that phthalide molecules are among the most important active substances in L. striatum [3][4][5] . Among these small molecules, senkyunolides may play an essential pharmacodynamic role in vivo because of their high oral bioavailability (BA) and have received extensive attention [6] .…”