scholarly journals Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents

MedChemComm ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 1900-1906 ◽  
Author(s):  
A. M. Omar ◽  
T. David ◽  
P. P. Pagare ◽  
M. S. Ghatge ◽  
Q. Chen ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Structural Modification ◽  
Oxygen Affinity ◽  
Cell Disease ◽  
Sickle Hemoglobin

The intracellular polymerization and the concomitant sickling processes, central to the pathology of sickle cell disease, can be mitigated by increasing the oxygen affinity of sickle hemoglobin (HbS).

scholarly journals Rational modification of vanillin derivatives to stereospecifically destabilize sickle hemoglobin polymer formation

2018 ◽  
Vol 74 (10) ◽  
pp. 956-964 ◽  
Author(s):  
Tanvi M. Deshpande ◽  
Piyusha P. Pagare ◽  
Mohini S. Ghatge ◽  
Qiukan Chen ◽  
Faik N. Musayev ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Biological Effects ◽  
Oxygen Affinity ◽  
Cell Disease ◽  
Sickle Hemoglobin ◽  
Polymer Formation ◽  
Promising Therapeutic Approach ◽  
Hb S

Increasing the affinity of hemoglobin for oxygen represents a feasible and promising therapeutic approach for sickle cell disease by mitigating the primary pathophysiological event,i.e.the hypoxia-induced polymerization of sickle hemoglobin (Hb S) and the concomitant erythrocyte sickling. Investigations on a novel synthetic antisickling agent, SAJ-310, with improved and sustained antisickling activity have previously been reported. To further enhance the biological effects of SAJ-310, a structure-based approach was employed to modify this compound to specifically inhibit Hb S polymer formation through interactions which perturb the Hb S polymer-stabilizing αF-helix, in addition to primarily increasing the oxygen affinity of hemoglobin. Three compounds, TD-7, TD-8 and TD-9, were synthesized and studied for their interactions with hemoglobin at the atomic level, as well as their functional and antisickling activitiesin vitro. X-ray crystallographic studies with liganded hemoglobin in complex with TD-7 showed the predicted mode of binding, although the interaction with the αF-helix was not as strong as expected. These findings provide important insights and guidance towards the development of molecules that would be expected to bind and make stronger interactions with the αF-helix, resulting in more efficacious novel therapeutics for sickle cell disease.

EFFECT OF BW12C ON OXYGEN AFFINITY OF HAEMOGLOBIN IN SICKLE-CELL DISEASE

The Lancet ◽  
1986 ◽  
Vol 327 (8485) ◽  
pp. 831-834 ◽  
Author(s):  
A.J. Keidan ◽  
R.D. White ◽  
E.R. Huehns ◽  
I.M. Franklin ◽  
M. Joy ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Oxygen Affinity ◽  
Cell Disease

scholarly journals Impact of voxelotor (GBT440) on unconjugated bilirubin and jaundice in sickle cell disease

2018 ◽  
Vol 10 (2) ◽  
Author(s):  
Paul Telfer ◽  
Irene Agodoa ◽  
Kathleen M. Fox ◽  
Laurie Burke ◽  
Timothy Mant ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Oxygen Affinity ◽  
Well Being ◽  
Unconjugated Bilirubin ◽  
Cell Disease ◽  
Case Patient ◽  
Disease Manifestation ◽  
Patient Reported ◽  
Hemoglobin Oxygen Affinity

For many patients with sickle cell disease (SCD), jaundice is a significant clinical disease manifestation that impacts on patient well-being. We report a case of a patient with SCD and chronic jaundice treated with voxelotor (GBT440), a novel small molecule hemoglobin oxygen affinity modulator and potential disease-modifying therapy for SCD. The case patient is a 27- year-old Black male with a long history of SCD with clinical jaundice and scleral icterus. After starting voxelotor, the patient reported that his jaundice cleared within one week, and that he felt much better with more energy, and was relieved after his eyes cleared. Voxelotor reduced bilirubin and unconjugated bilirubin (by up to 76%), and hemoglobin improved from 9.9 g/dL at baseline to 11.1 g/dL at 90 days. Jaundice impacts many adults with SCD, significantly impacting self-image. Voxelotor treatment reduced bilirubin levels and improved jaundice, resulting in an improved sense of well-being in our case patient.

scholarly journals Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 144
Author(s):  
Olivia Edwards ◽  
Alicia Burris ◽  
Josh Lua ◽  
Diana J. Wilkie ◽  
Miriam O. Ezenwa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Cells ◽  
Cell Disease ◽  
Free Hemoglobin ◽  
Cerebral Tissue ◽  
Sickle Hemoglobin ◽  
Haptoglobin Polymorphism

This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology. Hp is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. The role of Hp in patients with SCD is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD. Due to the malformed red blood cells of sickle hemoglobin S, blockage of blood flow is much more prevalent in patients with SCD. This review is the first to evaluate the role of the Hp polymorphism in the incidence of stroke in patients with SCD. Overall, the data compiled in this review suggest that further studies should be conducted to reveal and evaluate potential clinical advancements for gene therapy and Hp infusions.

HENNA (Lawsonia inermis) A MEDICINAL HERB EFFECTIVE IN SICKLE CELL DISEASE

2021 ◽  
pp. 01-04
Author(s):  
KRISHNA KUMAR ◽  
Nitish Kumar ◽  
Amresh gupta ◽  
Arpita singh ◽  
Pandey Swarnima ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Oxygen Affinity ◽  
Common Disease ◽  
Cell Disease ◽  
Lawsonia Inermis ◽  
Sodium Bisulphite ◽  
Sickle Cells

Sickle cell anemia is a common disease in Oman country. In this disease, sickle-shaped cells are formed. These cells interrupt blood vessels and cause a reduction in oxygen transportation. It was founded that henna (Lawsonia inermis) can prohibit the formation of sickle cells. The Lawsone (2-Hydroxy-1,4-Naphthoquinone) is the constituents of henna which is responsible for the anti-sickling activity, by increasing the oxygen affinity of red blood cells. Hena has the anti-sickling activity which is proved by incubating aqueous and methanolic henna extracts with sickle cell disease patient's whole blood. Then for reduction to oxygen tension 2%, sodium bisulphite was added. Therefore, the percentage of sickled cells to normal red blood cells was observed at 30 minutes intervals. Henna proved a delay in the sickling process in 84% of the tested samples. Both extracts(aqueous and methanolic henna) can delay sickling for about an hour.

Alterations of Hemoglobin Fractionation in a Sickle Cell Disease Patient on Voxelotor Therapy

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S100-S101
Author(s):  
S S Karimi ◽  
H Ni ◽  
L L Hsu
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Exchange Transfusion ◽  
Recent Literature ◽  
Disease Patient ◽  
Oxygen Affinity ◽  
Treatment Modalities ◽  
Cell Disease ◽  
Low Oxygen ◽  
Hydroxyurea Treatment

Abstract Introduction/Objective Voxelotor is a molecule that allosterically binds to the alpha-chain of hemoglobin, resulting in increased oxygen affinity. This allosteric inhibition leads to prevention of hemoglobin polymerization and sickling of red blood cells in response to low oxygen tension. Voxelotor has been used to treat patients with Sickle Cell Disease (SCD) and recent literature indicates it may contribute to complex hemoglobin fractionation (HF) elution patterns. We report a novel case of a SCD patient on concurrent Hydroxyurea, Voxelotor and chronic RBC exchange transfusion treatment and discuss the implications of these three treatment modalities on HF and monitoring of SCD. Methods A 17-year-old female with SCD complicated by frequent vaso-occlusive crisis, and avascular necrosis managed with chronic RBC exchange and Hydroxyurea. Her HF prior to initiation of Voxelotor treatment showed 3.2% HbA2, 51% HbA, 6.0% HbF, and 41% HbS. Voxelotor therapy was initiated at 1500mg/day and HF was performed 10 days later. Whole blood was collected and subjected to High Performance Liquid Chromatography (HPLC) with reflex to RBC solubility and Capillary Electrophoresis. Results HF performed post-Voxelotor therapy revealed positive sickle solubility with a complex pattern of 2.7% HbA2, 49.2% HbA, 5.3% HbF, 15.7% HbS, 0% HbC, and two additional peaks of a 6.3% peak in the window-D region (retention time of 4.34) and 20.8% of an atypical Hb peak pattern (at the retentuin time of 4.18). The results reflected a complex HF of a HbSS patient on concurrent chronic RBC exchange transfusion, hydroxyurea therapy, and Voxelotor treatment. Post Voxelotor-therapy HF revealed a reduction in HbS from 41% to 15.7% with the emergence of two additional peaks. Chronic RBC exchange transfusion and Hydroxyurea treatment account for the observed fractionation of HbA and HbF, respectively. Based on recent literature, we attribute the emergence of the two additional peaks to Voxelotor therapy. All three therapies led to reduction in HbS. Conclusion Routine HF serves as an essential modality in diagnosis and monitoring of SCD. Voxelotor treatment alters the HF profile and may cause difficulty for interpretation. With the emergence of novel therapies, it is imperative for clinicians to provide medication information to clinical laboratories and pathologists to be fully aware of the effects of current treatments to correctly interpret and monitor SCD.

scholarly journals Rapid and inefficient kinetics of sickle hemoglobin fiber growth

2019 ◽  
Vol 5 (3) ◽  
pp. eaau1086 ◽  
Author(s):  
Brian T. Castle ◽  
David J. Odde ◽  
David K. Wood
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Self Assembly ◽  
Assembly Process ◽  
Cell Disease ◽  
Spatiotemporal Resolution ◽  
Fiber Assembly ◽  
Sickle Hemoglobin ◽  
Order Of Magnitude ◽  
Blood Cell Morphology

In sickle cell disease, the aberrant assembly of hemoglobin fibers induces changes in red blood cell morphology and stiffness, which leads to downstream symptoms of the disease. Therefore, understanding of this assembly process will be important for the treatment of sickle cell disease. By performing the highest spatiotemporal resolution measurements (55 nm at 1 Hz) of single sickle hemoglobin fiber assembly to date and combining them with a model that accounts for the multistranded structure of the fibers, we show that the rates of sickle hemoglobin addition and loss have been underestimated in the literature by at least an order of magnitude. These results reveal that the sickle hemoglobin self-assembly process is very rapid and inefficient (4% efficient versus 96% efficient based on previous analyses), where net growth is the small difference between over a million addition-loss events occurring every second.

scholarly journals Metabolomic and molecular insights into sickle cell disease and innovative therapies

2019 ◽  
Vol 3 (8) ◽  
pp. 1347-1355 ◽  
Author(s):  
Morayo G. Adebiyi ◽  
Jeanne M. Manalo ◽  
Yang Xia
Keyword(s):  
Sickle Cell Disease ◽  
Disease Progression ◽  
Sickle Cell ◽  
Intracellular Signaling ◽  
Metabolic Reprogramming ◽  
Flux Analysis ◽  
High Morbidity ◽  
Cell Disease ◽  
Sickle Hemoglobin

Abstract Sickle cell disease (SCD) is an autosomal-recessive hemolytic disorder with high morbidity and mortality. The pathophysiology of SCD is characterized by the polymerization of deoxygenated intracellular sickle hemoglobin, which causes the sickling of erythrocytes. The recent development of metabolomics, the newest member of the “omics” family, has provided a powerful new research strategy to accurately measure functional phenotypes that are the net result of genomic, transcriptomic, and proteomic changes. Metabolomics changes respond faster to external stimuli than any other “ome” and are especially appropriate for surveilling the metabolic profile of erythrocytes. In this review, we summarize recent pioneering research that exploited cutting-edge metabolomics and state-of-the-art isotopically labeled nutrient flux analysis to monitor and trace intracellular metabolism in SCD mice and humans. Genetic, structural, biochemical, and molecular studies in mice and humans demonstrate unrecognized intracellular signaling pathways, including purinergic and sphingolipid signaling networks that promote hypoxic metabolic reprogramming by channeling glucose metabolism to glycolysis via the pentose phosphate pathway. In turn, this hypoxic metabolic reprogramming induces 2,3-bisphosphoglycerate production, deoxygenation of sickle hemoglobin, polymerization, and sickling. Additionally, we review the detrimental role of an impaired Lands’ cycle, which contributes to sickling, inflammation, and disease progression. Thus, metabolomic profiling allows us to identify the pathological role of adenosine signaling and S1P-mediated erythrocyte hypoxic metabolic reprogramming and hypoxia-induced impaired Lands' cycle in SCD. These findings further reveal that the inhibition of adenosine and S1P signaling cascade and the restoration of an imbalanced Lands' cycle have potent preclinical efficacy in counteracting sickling, inflammation, and disease progression.

scholarly journals Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

2017 ◽  
Vol 114 (5) ◽  
pp. E689-E696 ◽  
Author(s):  
Quan Li ◽  
Eric R. Henry ◽  
James Hofrichter ◽  
Jeffrey F. Smith ◽  
Troy Cellmer ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Cell Volume ◽  
Sickle Cell ◽  
Kinetic Method ◽  
Oxygen Affinity ◽  
Hemoglobin Concentration ◽  
Fiber Formation ◽  
Automated Image Analysis ◽  
Cell Disease ◽  
Kinetic Assay

Although it has been known for more than 60 years that the cause of sickle cell disease is polymerization of a hemoglobin mutant, hydroxyurea is the only drug approved for treatment by the US Food and Drug Administration. This drug, however, is only partially successful, and the discovery of additional drugs that inhibit fiber formation has been hampered by the lack of a sensitive and quantitative cellular assay. Here, we describe such a method in a 96-well plate format that is based on laser-induced polymerization in sickle trait cells and robust, automated image analysis to detect the precise time at which fibers distort (“sickle”) the cells. With this kinetic method, we show that small increases in cell volume to reduce the hemoglobin concentration can result in therapeutic increases in the delay time prior to fiber formation. We also show that, of the two drugs (AES103 and GBT440) in clinical trials that inhibit polymerization by increasing oxygen affinity, one of them (GBT440) also inhibits sickling in the absence of oxygen by two additional mechanisms.

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