Emerging drug targets for sickle cell disease: shedding light on new knowledge and advances at the molecular level

by Selleckchem | Mar 10 2023

Introduction: In sickle cell disease (SCD), a single amino acid substitution at β6 of the haemoglobin (Hb) chain replaces glutamate with valine, forming HbS instead of the normal adult HbA. Loss of a negative charge, and the conformational change in deoxygenated HbS molecules, enables formation of HbS polymers. These not only distort red cell morphology but also have other profound effects so that this simple aetiology belies a complex pathogenesis with multiple complications. Although SCD represents a common severe inherited disorder with life-long consequences, approved treatments remain inadequate. Hydroxyurea is currently the most effective, with a handful of newer treatments, but there remains a real need for novel, efficacious therapies.

Areas covered: This review summarises important early events in pathogenesis to highlight key targets for novel treatments.

Expert opinion: A thorough understanding of early events in pathogenesis closely associated with the presence of HbS is the logical starting point for identification of new targets rather than concentrating on more downstream effects. We discuss ways of reducing HbS levels, reducing the impact of HbS polymers, and of membrane events perturbing cell function, and suggest using the unique permeability of sickle cells to target drugs specifically into those more severely compromised.

Comments：

Sickle cell disease (SCD) is a complex genetic disorder that results from a single amino acid substitution in the β-globin chain of hemoglobin. This substitution leads to the formation of hemoglobin S (HbS), which is prone to polymerization, resulting in the sickling of red blood cells (RBCs) and a range of downstream pathophysiological events. While there are currently a handful of approved treatments for SCD, these remain inadequate, and there is a real need for novel, efficacious therapies.

To identify new targets for treatment, it is crucial to understand the early events in the pathogenesis of SCD that are closely associated with the presence of HbS. These events include HbS polymerization, membrane perturbations, and oxidative stress. One approach is to focus on reducing HbS levels, which could be achieved by promoting fetal hemoglobin (HbF) production or by inhibiting HbS synthesis. Another approach is to reduce the impact of HbS polymers on RBCs, which could be achieved by promoting HbS solubility or inhibiting HbS polymerization. Additionally, targeting membrane events perturbing cell function, such as reducing phosphatidylserine exposure or inhibiting potassium efflux, may also be a viable approach.

One unique characteristic of sickle cells is their increased permeability compared to normal RBCs. This feature could be exploited to develop drugs that target sickle cells specifically, potentially leading to more efficacious treatments with fewer side effects.
In conclusion, a thorough understanding of the early events in the pathogenesis of SCD is essential for identifying new targets for treatment. By focusing on reducing HbS levels, reducing the impact of HbS polymers, and targeting membrane events perturbing cell function, we may be able to develop more efficacious treatments for SCD. Additionally, exploiting the unique permeability of sickle cells to develop targeted therapies may be a promising avenue for future research.