Metabolic Reprogramming in Sickle Cell Diseases: Pathophysiology and Drug Discovery Opportunities

Abstract

Sickle cell disease (SCD) is a genetic disorder that affects millions of individuals worldwide. Chronic anemia, hemolysis, and vasculopathy are associated with SCD, and their role has been well characterized. These symptoms stem from hemoglobin (Hb) polymerization, which is the primary event in the molecular pathogenesis of SCD and contributes to erythrocyte or red blood cell (RBC) sickling, stiffness, and vaso-occlusion. The disease is caused by a mutation at the sixth position of the β-globin gene, coding for sickle Hb (HbS) instead of normal adult Hb (HbA), which under hypoxic conditions polymerizes into rigid fibers to distort the shapes of the RBCs. Only a few therapies are available, with the universal effectiveness of recently approved therapies still being monitored. In this review, we first focus on how sickle RBCs have altered metabolism and then highlight how this understanding reveals potential targets involved in the pathogenesis of the disease, which can be leveraged to create novel therapeutics for SCD.

X-ray crystallography and sickle cell disease drug discovery—a tribute to Donald Abraham

“…With the discovery that CFA binds to the central water cavity of DeoxyHb to stabilize the T-state Hb and pharmacologically increase O 2 delivery to tissue, ( Abraham et al, 1983b ), scientists, and most notably Abraham recognized the importance of structure-based drug design of synthetic allosteric effectors that would have high oral bioavailability, easily traverse RBC, bind with high affinity to Hb, and potently increase Hb oxygen delivery to tissues. Physiologically Hb with a bound 2,3-DPG releases 25%–40% of oxygen, ( Safo and Bruno, 2011 ; Ahmed et al, 2020 ; Alramadhani et al, 2022 ), and it was expected that more potent right-shifters would lead to an even more increase of oxygen to tissues, and potentially useful for treating hypoxic underlying diseases, such as angina, stroke, trauma, blood storage, and to enhance radiation treatment of hypoxic tumors ( Randad et al, 1991 ; Abraham et al, 1992 ; Mehta and Khuntia, 2005 ; Rosenberg and Knox, 2006 ; Stea et al, 2006 ; Safo and Bruno, 2011 ). The discovery of Efaproxiral involved careful iterative targeted modifications starting from earlier studied analogs, e.g., CFA and bezafibrate through both structure activity relationship (SAR) and SBDD using X-ray crystallography ( Abraham et al, 1992 ; Phelps Grella et al, 2000 ; Safo et al, 2002a ; Youssef et al, 2002 ; Safo and Bruno, 2011 ).…”

Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease

“…1,5,10,14 Several glycolytic enzymes and the Rapoport-Luebering shunt are activated in RBCs under hypoxic conditions, leading to increased 2,3 diphosphoglycerate (2,3-DPG) production. 15,16 In sickle RBCs, increased 2,3-DPG reduces the oxygen (O 2 ) affinity of HbS, causing increased dissociation of O 2 at higher partial pressure of dissolved O 2 (pO 2 ) compared with normal RBCs. 1,15 The increase in deoxygenated HbS induces Hb polymerization and precipitates a cascade of pathologic events, including RBC sickling, hemolysis, endothelial dysfunction, and abnormal activation of inflammatory, coagulation, and oxidative pathways.…”

“…15,16 In sickle RBCs, increased 2,3-DPG reduces the oxygen (O 2 ) affinity of HbS, causing increased dissociation of O 2 at higher partial pressure of dissolved O 2 (pO 2 ) compared with normal RBCs. 1,15 The increase in deoxygenated HbS induces Hb polymerization and precipitates a cascade of pathologic events, including RBC sickling, hemolysis, endothelial dysfunction, and abnormal activation of inflammatory, coagulation, and oxidative pathways. 1 This causes oxidative stress, vaso-occlusion, and tissue ischemia-reperfusion injury.…”

“…1,3,9 Concurrently with increased intracellular 2,3-DPG in sickle RBCs, adenosine triphosphate (ATP) levels are reduced. 17 ATP is necessary for normal ion channel function and RBC membrane homeostasis; 15,18 pathway may lead to clinical benefit in patients with SCD and was also relatively well tolerated and associated with improvements in Hb concentration and markers of hemolysis. 23,24 We report here the first study of etavopivat in patients with SCD.…”