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Sickle cell and GBT440

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https://www.readbyqxmd.com/read/30046415/impact-of-voxelotor-gbt440-on-unconjugated-bilirubin-and-jaundice-in-sickle-cell-disease
#1
Paul Telfer, Irene Agodoa, Kathleen M Fox, Laurie Burke, Timothy Mant, Marzena Jurek, Margaret Tonda, Josh Lehrer-Graiwer
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...
May 14, 2018: Hematology Reports
https://www.readbyqxmd.com/read/30046411/gbt440-reverses-sickling-of-sickled-red-blood-cells-under-hypoxic-conditions-in-vitro
#2
Kobina Dufu, Donna Oksenberg
Sickle cell disease is characterized by hemolytic anemia, vasoocclusion and early mortality. Polymerization of hemoglobin S followed by red blood cell sickling and subsequent vascular injury are key events in the pathogenesis of sickle cell disease. Sickled red blood cells are major contributors to the abnormal blood rheology, poor microvascular blood flow and endothelial injury in sickle cell disease. Therefore, an agent that can prevent and or reverse sickling of red blood cells, may provide therapeutic benefit for the treatment of sickle cell disease...
May 14, 2018: Hematology Reports
https://www.readbyqxmd.com/read/29660913/gbt440-improves-red-blood-cell-deformability-and-reduces-viscosity-of-sickle-cell-blood-under-deoxygenated-conditions
#3
Kobina Dufu, Mira Patel, Donna Oksenberg, Pedro Cabrales
BACKGROUND: In sickle cell disease (SCD), polymerization of hemoglobin S (HbS) leads to the formation of rigid, non-deformable sickled RBCs. Loss of RBC deformability, sickling and irreversible membrane damage causes abnormal blood rheology, and increases viscosity which contributes to vasoocclusion and other SCD pathophysiology. GBT440 (generic name voxelotor) is a novel anti-polymerization and anti-sickling agent currently undergoing clinical evaluation for the treatment of SCD. OBJECTIVE: The purpose of this study was to determine the effects of GBT440 on deformability of sickle RBCs (SS RBCs) and the hyperviscosity of sickle cell blood (SS blood)...
April 13, 2018: Clinical Hemorheology and Microcirculation
https://www.readbyqxmd.com/read/28337324/discovery-of-gbt440-an-orally-bioavailable-r-state-stabilizer-of-sickle-cell-hemoglobin
#4
Brian Metcalf, Chihyuan Chuang, Kobina Dufu, Mira P Patel, Abel Silva-Garcia, Carl Johnson, Qing Lu, James R Partridge, Larysa Patskovska, Yury Patskovsky, Steven C Almo, Matthew P Jacobson, Lan Hua, Qing Xu, Stephen L Gwaltney, Calvin Yee, Jason Harris, Bradley P Morgan, Joyce James, Donghong Xu, Athiwat Hutchaleelaha, Kumar Paulvannan, Donna Oksenberg, Zhe Li
We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 ( 36 ), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations...
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28096387/kinetic-assay-shows-that-increasing-red-cell-volume-could-be-a-treatment-for-sickle-cell-disease
#5
Quan Li, Eric R Henry, James Hofrichter, Jeffrey F Smith, Troy Cellmer, Emily B Dunkelberger, Belhu B Metaferia, Stacy Jones-Straehle, Sarah Boutom, Garrott W Christoph, Terri H Wakefield, Mary E Link, Dwayne Staton, Erica R Vass, Jeffery L Miller, Matthew M Hsieh, John F Tisdale, William A Eaton
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...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27757216/gbt440-inhibits-sickling-of-sickle-cell-trait-blood-under-in-vitro-conditions-mimicking-strenuous-exercise
#6
Kobina Dufu, Josh Lehrer-Graiwer, Eleanor Ramos, Donna Oksenberg
In sickle cell trait (SCT), hemoglobin A (HbA) and S (HbS) are co-expressed in each red blood cell (RBC). While homozygous expression of HbS (HbSS) leads to polymerization and sickling of RBCs resulting in sickle cell disease (SCD) characterized by hemolytic anemia, painful vaso-occlusive episodes and shortened life-span, SCT is considered a benign condition usually with minor or no complications related to sickling. However, physical activities that cause increased tissue oxygen demand, dehydration and/or metabolic acidosis leads to increased HbS polymerization and life-threatening complications including death...
September 28, 2016: Hematology Reports
https://www.readbyqxmd.com/read/27605087/new-developments-in-anti-sickling-agents-can-drugs-directly-prevent-the-polymerization-of-sickle-haemoglobin-in-vivo
#7
REVIEW
Esther Oder, Martin K Safo, Osheiza Abdulmalik, Gregory J Kato
The hallmark of sickle cell disease is the polymerization of sickle haemoglobin due to a point mutation in the β-globin gene (HBB). Under low oxygen saturation, sickle haemoglobin assumes the tense (T-state) deoxygenated conformation that can form polymers, leading to rigid erythrocytes with impaired blood vessel transit, compounded or initiated by adhesion of erythrocytes to endothelium, neutrophils and platelets. This process results in vessel occlusion and ischaemia, with consequent acute pain, chronic organ damage, morbidity and mortality...
October 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27410726/gbt440-increases-haemoglobin-oxygen-affinity-reduces-sickling-and-prolongs-rbc-half-life-in-a-murine-model-of-sickle-cell-disease
#8
EDITORIAL
Frank A Ferrone
No abstract text is available yet for this article.
August 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27378309/gbt440-increases-haemoglobin-oxygen-affinity-reduces-sickling-and-prolongs-rbc-half-life-in-a-murine-model-of-sickle-cell-disease
#9
Donna Oksenberg, Kobina Dufu, Mira P Patel, Chihyuan Chuang, Zhe Li, Qing Xu, Abel Silva-Garcia, Chengjing Zhou, Athiwat Hutchaleelaha, Larysa Patskovska, Yury Patskovsky, Steven C Almo, Uma Sinha, Brian W Metcalf, David R Archer
A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs...
October 2016: British Journal of Haematology
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