Investigation of Sickle‐Cell Haemoglobin Polymerisation under Electrochemical Control

Iqbal, Zeshan; Li, Matthew; McKendry, Rachel A.; Horton, Michael A.; Caruana, Daren J.

doi:10.1002/cphc.201300203

Cited by 5 publications

(6 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A prevailing doubt about the suitability of the HbS molecule as target for drug development has to do with the perceived limitation imposed by its high content level in man (about 450g) [61], suggesting that an intolerably high dose of antisickling compound would be required to achieve clinically useful degrees of inhibition [85]. This perception was mostly based on an aggregation model built on the assumption of a highly efficient nucleation dependent HbS polymerization process believed to involve two nucleation stages, beginning with a rate-limiting homogeneous nucleation, followed by a highly efficient heterogeneous nucleation phase [86,87]. For aggregation to occur, the delay time associated with the homogeneous nucleation should necessarily be shorter than re-oxygenation circulation time, which is the time required for the hemoglobin to pass through the blood vessels and The hemoglobin tetramer is represented as a circle, such that one quarter corresponds to one protein subunit using the same coloring as in Figure 1.…”

Section: Hbs Aggregation Is An Inefficient Processmentioning

confidence: 99%

“…They bind to the N-terminal valine (and possibly lysine) residues of the α-globin chains of HbS ( Figure 4) [98], forming a reversible Schiff-base adduct which stabilizes the R-state and/or destabilizes the T-state, increasing hemoglobin solubility, and thus inhibiting HbS aggregation. Iqbal et al employed an electrochemistry-based technique to investigate HbS polymerization in the presence of vanillin and 5-HMF [86]. At HbS concentrations of 100 mg/mL, aggregation inhibition was obtained for vanillin concentrations corresponding to 0.5:1, 1:1, and 10:1 mole ratios relative to HbS.…”

Section: Antisickling Effect and Hbs Conformationmentioning

confidence: 99%

See 1 more Smart Citation

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

2019

View full text Add to dashboard Cite

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...

show abstract

Section: Hbs Aggregation Is An Inefficient Processmentioning

confidence: 99%

Section: Antisickling Effect and Hbs Conformationmentioning

confidence: 99%

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

2019

View full text Add to dashboard Cite

show abstract

“…Polymerization in SCD is a process triggered by a phenomenon known as nucleation in which a number of molecules come together within an embryo of the new phase that resembles a first transition phase similar to a gas-solid transformation [88,89]. The nucleation progressively progresses through the initial fiber growth and its branching, due to the secondary nucleation of new fibers on top of the existing ones, as if it were a double nucleation [77,88,90,91].…”

Section: Thalassemia and Other Hemolytic Anemiasmentioning

confidence: 99%

Sickle Cell Disease: A Genetic Disorder of Beta-Globin

Cordovil¹

2018

Thalassemia and Other Hemolytic Anemias

View full text Add to dashboard Cite

Sickle cell disease (SCD) is a structural and monogenetic genetic disorder due to a mutation that occurs in the globin β-chain, resulting in the formation of hemoglobin S (Hb S), a protein composed of two normal, and two β-type mutant chains. Estimates indicate that the prevalence among live births is 4.4% in the world. The difficulty in circulating the sickle cell, its interaction with endothelial cells, leukocytes, platelets, endothelial dysfunction, and the abnormal expression of adhesion molecules permeate the beginning of the blood vessel occlusion process as well as pathophysiological aspects of SCD. Among the secondary complications are the stroke, pulmonary hypertension, leg ulcer, renal disorders, and all complications associated with vascular dysfunction. Clinical and biochemical markers of disease severity can be used to predict risk, prevent complications, and increase the expectation and quality of life of the SCD population. The entire scenario generated by Hb S has implications for the health and social inclusion of patients, so the treatment of the person with SCD needs an approach focused on the prevention of these complications in an individualized way.

show abstract

“…An electrochemistry based study designed a technique to control and monitor the polymerization of sickle-cell hemoglobin (HbS) by looking the change in turbidity during the depletion of oxygen in a small volume of custom-built thinlayer electrochemical cell. The cell allowed the investigation of HbS polymerization as a function of HbS concentration, temperature and solution pH [11]. Due to bad impact of sickle cell disease, this research work got attention on the study of thermal and transport property of sickle hemoglobin and normal hemoglobin protein.…”

Section: Introductionmentioning

confidence: 99%

Thermal properties of normal and sickled hemoglobin protein

Powrel¹,

Adhikari²

2021

BIBECHANA

View full text Add to dashboard Cite

Thermodynamic properties of sickled and normal hemoglobin protein are considered within the framework of classical molecular dynamics. Here we have studied the specific heat capacity and RMSD (Root Mean Square Deviation) of both types of hemoglobin protein. Our investigation reveals that the specific heat capacity and RMSD for oxygenated hemoglobin protein is higher than those of de-oxygenated sickle hemoglobin protein. It is also observed that the specific heat capacity and RMSD values of sickle hemoglobin protein decrease with a rise in temperature. BIBECHANA 18 (2021) 140-148

show abstract

Investigation of Sickle‐Cell Haemoglobin Polymerisation under Electrochemical Control

Cited by 5 publications

References 55 publications

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

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

Sickle Cell Disease: A Genetic Disorder of Beta-Globin

Thermal properties of normal and sickled hemoglobin protein

Contact Info

Product

Resources

About