Novel Inhibitors of the Gardos Channel for the Treatment of Sickle Cell Disease

McNaughton‐Smith, Grant; Burns, James F.; Stocker, Jonathan W.; Rigdon, Gregory C; Creech, Christopher; Arrington, Susan; Shelton, Tara; Franceschi, Lucia De

doi:10.1021/jm070663s

Cited by 59 publications

(45 citation statements)

References 28 publications

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“…It has been shown that repeated cycles of sickling and unsickling lead to activation of the Gardos channel (K Ca 3.1), a calcium-activated potassium efflux channel, which is a major factor in RBC dehydration and reduced deformability and increased fragility [4], [5]. Dehydration increases the intracellular concentration of Hb which enhances the rate of polymerization [6], [7], [8]. Red blood cell fragility results in hemolysis in SCD and other hemolytic diseases [9], [10], diabetes, and transfusion of older stored blood; which in turn can lead directly to inflammation [11], [12], [13], and platelet activation [14], [15], [16], [17], [18], [19], [20].…”

Section: Introductionmentioning

confidence: 99%

Potential therapeutic action of nitrite in sickle cell disease

et al. 2017

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Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions, increasing rigidity, fragility, calcium influx-mediated dehydration, and adhesivity of red blood cells. Increased red cell fragility results in hemolysis, which reduces nitric oxide (NO) bioavailability, and induces platelet activation and inflammation leading to adhesion of circulating blood cells. Nitric Oxide inhibits adhesion and platelet activation. Nitrite has emerged as an attractive therapeutic agent that targets delivery of NO activity to areas of hypoxia through bioactivation by deoxygenated red blood cell hemoglobin. In this study, we demonstrate anti-platelet activity of nitrite at doses achievable through dietary interventions with comparison to similar doses with other NO donating agents. Unlike other NO donating agents, nitrite activity is shown to be potentiated in the presence of red blood cells in hypoxic conditions. We also show that nitrite reduces calcium associated loss of phospholipid asymmetry that is associated with increased red cell adhesion, and that red cell deformability is also improved. We show that nitrite inhibits red cell adhesion in a microfluidic flow-channel assay after endothelial cell activation. In further investigations, we show that leukocyte and platelet adhesion is blunted in nitrite-fed wild type mice compared to control after either lipopolysaccharide- or hemolysis-induced inflammation. Moreover, we demonstrate that nitrite treatment results in a reduction in adhesion of circulating blood cells and reduced red blood cell hemolysis in humanized transgenic sickle cell mice subjected to local hypoxia. These data suggest that nitrite is an effective anti-platelet and anti-adhesion agent that is activated by red blood cells, with enhanced potency under physiological hypoxia and in venous blood that may be useful therapeutically.

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Section: Introductionmentioning

confidence: 99%

Potential therapeutic action of nitrite in sickle cell disease

et al. 2017

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“…These compounds prevented hemolysis and sickle cell formation in vivo, in a transgenic mouse model [69,70].…”

Section: Inhibition Of Erythrocyte Dehydrationmentioning

confidence: 98%

Sickle Cell Disease – Current Treatment and New Therapeutical Approaches

Melo¹,

Ercolin²,

Chelucci³

et al. 2015

Inherited Hemoglobin Disorders

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Sickle cell disease (SCD) is one of the most common genetic disorders worldwide. It is caused by a point mutation that changes glutamic acid (Glu6) to valine (Val6) in the β chain of hemoglobin. Vaso-occlusion is the most well-known problem associated with SCD. Despite recent advances in understanding the disease at the molecular level, few therapeutic strategies are available. Hydroxyurea is the only drug currently approved by the U.S. Food and Drug Administration for the disease, and it has serious adverse effects and lack of efficacy in some patients. However, new therapeutic approaches are under investigation in the hope of discovering new drugs to treat SCD.These include agents that: a) increase nitric oxide bioavailability; b) modify the rheological properties of the blood; c) bind covalently to hemoglobin; d) prevent hemoglobin dehydration; e) reduce iron overload; and f) induce the expression of gamma globin and fetal hemoglobin. In this chapter, we discuss the current treatment of SCD and the advances made in medicinal chemistry to find new drugs to treat this neglected hematological disease.

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“…Other potential indications for KCa3.1 inhibition are sickle cell disease (Brugnara, 2003) and secretory diarrhea in humans and farm animals (Rufo et al, 1997). Research groups in both the pharmaceutical industry and academia have identified several classes of potent and selective KCa3.1 blockers including the triarylmethanes senicapoc (triarylmethanes 2,2-bis-(4-fluorophenyl)-2-phenylacetamide) (McNaughton-Smith et al, 2008) and diphenylmethyl]-1H-pyrazole) , the benzothiazione NS6180 (4- [[3-(trifluoromethyl)phenyl]methyl]-2H-1,4-benzothiazin-3(4H)-one) (Strøbaek et al, 2013), and a series of dihydropyridine isosteric 4-phenyl-pyrans and cyclohexadienes (Urbahns et al, 2005). Senicapoc, which was in phase-3 clinical trials for sickle cell anemia, where it failed for lack of efficacy in reducing the number of painful sickling attacks (Ataga et al, 2011), demonstrated that KCa3.1 inhibitors are safe and well tolerated in humans.…”

Section: Introductionmentioning

confidence: 99%