2,3-Diphosphoglycerate and intracellular pH as interdependent determinants of the physiologic solubility of deoxyhemoglobin S

Poillon, William N.; Kim, Bak C.

doi:10.1182/blood.v76.5.1028.1028

Cited by 63 publications

(21 citation statements)

References 41 publications

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“…BPGM also reversibly acts to hydrolyze 2,3-BPG to 3-PGA, which then re-enters the main glycolytic pathway. 2,3-BPG, as mentioned earlier, has a significant contribution to SCD pathogenesis due to its elevation in sickle RBCs [2,12,13,[15][16][17]. Moving forward, BPGM and/or GAPDH could potentially serve as a target to modulate the concentration of 2,3-BPG in erythrocyte with a therapeutic effect on SCD.…”

Section: Embden-meyerhof-parnas Pathway (Emp)mentioning

confidence: 84%

“…Several studies have implicated 2,3-BPG in the pathogenesis of SCD [2,[12][13][14][15][16][17][18]. The high level of 2,3-BPG in sickle RBCs has been shown to increase the hypoxia-induced HbS polymerization and subsequently RBC sickling [2,37].…”

Section: 3-bpg In Scd Pathogenesis and Potential Targets For Scd Ther...mentioning

confidence: 99%

“…Consistently, mutations that break some of these secondary contacts, for example, αAsn78→Lys (Hb Stanleyville), βAsp73→Asn (Hb Korle Bu), or βAsp73→Val (Hb Mobile), increase the solubility of deoxyHbS, thereby reducing the severity of the disease [2,4,[8][9][10]. Interestingly, 2,3-BPG, which is found in high concentration in sickle erythrocytes or red blood cells (RBCs), in conjunction with the hypoxia-responsive signaling molecule, sphingosine 1-phosphate (S1P) [11], adversely decreases HbS affinity for oxygen, leading to an increased concentration of the polymer-forming low-O 2 -affinity deoxyHbS [12][13][14][15][16][17][18]. Polymerization results in the formation of a helical structure, which ultimately leads to the sickling of RBCs and impaired rheology of the blood [2,3,7,8,10].…”

Section: Introduction 1pathophysiology Of Sickle Cell Diseasementioning

confidence: 99%

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

Alramadhani

Aljahdali

Abdulmalik

et al. 2022

IJMS

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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.

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Section: Embden-meyerhof-parnas Pathway (Emp)mentioning

confidence: 84%

Section: 3-bpg In Scd Pathogenesis and Potential Targets For Scd Ther...mentioning

confidence: 99%

Section: Introduction 1pathophysiology Of Sickle Cell Diseasementioning

confidence: 99%

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

Alramadhani

Aljahdali

Abdulmalik

et al. 2022

IJMS

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“…The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12-and 15-mers under consideration in recent years.Molecules 2019, 24, 4551 2 of 23 with hemoglobin reduces HbS solubility and promotes polymerization, also called sickling [3,4]. This ultimately leads to hampered O 2 binding and transport, impaired erythrocyte morphology and interaction with endothelial surfaces [5,6], premature erythrocyte rupture and anemia, painful vaso-occlusive crisis, a general poor health, and, in many cases, death [7][8][9][10][11].Despite growing understanding of the polymerization of HbS and its effects on red blood cells (RBCs), until very recently, only two drugs-hydroxyurea and L-glutamine-were approved by the United States (US) Food and Drug Administration (FDA) for the management of SCD [12].…”

mentioning

confidence: 99%

“…Molecules 2019, 24, 4551 2 of 23 with hemoglobin reduces HbS solubility and promotes polymerization, also called sickling [3,4]. This ultimately leads to hampered O 2 binding and transport, impaired erythrocyte morphology and interaction with endothelial surfaces [5,6], premature erythrocyte rupture and anemia, painful vaso-occlusive crisis, a general poor health, and, in many cases, death [7][8][9][10][11].…”

mentioning

confidence: 99%

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

2019

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Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12-and 15-mers under consideration in recent years.Molecules 2019, 24, 4551 2 of 23 with hemoglobin reduces HbS solubility and promotes polymerization, also called sickling [3,4]. This ultimately leads to hampered O 2 binding and transport, impaired erythrocyte morphology and interaction with endothelial surfaces [5,6], premature erythrocyte rupture and anemia, painful vaso-occlusive crisis, a general poor health, and, in many cases, death [7][8][9][10][11].Despite growing understanding of the polymerization of HbS and its effects on red blood cells (RBCs), until very recently, only two drugs-hydroxyurea and L-glutamine-were approved by the United States (US) Food and Drug Administration (FDA) for the management of SCD [12]. Hydroxyurea is the most widely employed drug treatment of sickle cell anemia in different age groups [13][14][15][16][17][18]. While its clinically observed efficacy has been attributed to different effects at the cellular level [19], the most important mechanism of action relates to its ability to induce the production of fetal hemoglobin (HbF), which does not polymerize, and to increase the total concentration of hemoglobin [20,21]. Hydroxyurea remains a viable treatment option for SCD, and the concern of toxicities associated with its administration has largely been limited to side effects that resolve with medication discontinuation [22][23][24][25][26]. There have, however, been certain reports of associated malignancies [27][28][29][30][31][32], but further investigations are needed to categorically confirm these [33]. L-glutamine is the second approved drug treatment [12,34]. While its mechanism of action is not known, and only suggested to involve a reduction of oxidative stress via elevation of the levels of reduced glutathione [35,36], it is clear that it has no effect on hemo...

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Therapeutic Strategies for the Treatment of Sickle Cell Disease

Aljahdali

Burnett

Abraham

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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There are many important new advances in the development of clinically viable therapeutic options to mitigate the pathophysiology of sickle cell disease (SCD). Some of the most promising new clinical candidates reported herein directly address the primary cause of the disease by allosterically modifying sickle hemoglobin (HbS). In particular, one family of small molecules stabilizes the high oxygen (O 2 )‐affinity R‐state of the protein, which, unlike the low O 2 ‐affinity T‐state, does not present the polymerization promoting βVal6 residue. Several compounds employing this mechanism are currently at various stages of preclinical and clinical investigations. Another series of compounds that engage in a covalent bond with the surface‐located residue βCys93 of HbS, and thus destabilize the T‐state to increase Hb affinity for oxygen, is currently under preclinical development. Furthermore, promising new compounds that, similar to hydroxyurea also induce fetal Hb production, are at various stages of clinical development. Finally, compounds that target the secondary pathophysiology of SCD, including those that counter the dehydration of sickle erythrocyte; endothelial adhesion and vasculature damage; nitroxide donors providing vasodilatory and anti‐inflammatory effects; and a myriad of anti‐inflammatory and anticoagulation candidate molecules, are also being investigated in early‐ and/or late‐stage clinical trials.

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2,3-Diphosphoglycerate and intracellular pH as interdependent determinants of the physiologic solubility of deoxyhemoglobin S

Cited by 63 publications

References 41 publications

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

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

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

Therapeutic Strategies for the Treatment of Sickle Cell Disease

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