The effect of the antisickling compoundGBT1118 on the permeability of red blood cells from patients with sickle cell anemia

Autor: John N. Brewin, Kobina Dufu, David C. Rees, David C.-Y. Lu, Anke Hannemann, Halima Al Balushi, Donna Oksenberg, John S. Gibson
Přispěvatelé: Hannemann, Anke [0000-0002-2925-1124], Gibson, John [0000-0001-6145-9139], Apollo - University of Cambridge Repository
Rok vydání: 2019
Předmět:
Cardiovascular Conditions
Disorders and Treatments
Niacinamide
Lysis
Genetic Conditions Disorders and Treatments
Physiology
Hemoglobin
Sickle
Ionophore
Anemia
Sickle Cell
potassium permeability
030204 cardiovascular system & hematology
Pharmacology
Hemolysis
Permeability
lcsh:Physiology
Pathogenesis
03 medical and health sciences
0302 clinical medicine
Antisickling Agents
Physiology (medical)
Membrane Physiology
medicine
Humans
cell volume
Original Research
Cell Size
chemistry.chemical_classification
Symporters
lcsh:QP1-981
Erythrocyte Membrane
hemic and immune systems
Transporter
Intermediate-Conductance Calcium-Activated Potassium Channels
medicine.disease
Sickle cell anemia
Oxygen
sickling
chemistry
GBT1118
Permeability (electromagnetism)
Benzaldehydes
Thiol
O2 affinity
030217 neurology & neurosurgery
Zdroj: Physiological Reports, Vol 7, Iss 6, Pp n/a-n/a (2019)
Physiological Reports
ISSN: 2051-817X
DOI: 10.14814/phy2.14027
Popis: Sickle cell anemia (SCA) is one of the commonest severe inherited disorders. Nevertheless, effective treatments remain inadequate and novel ones are avidly sought. A promising advance has been the design of novel compounds which react with hemoglobin S (HbS) to increase oxygen (O2) affinity and reduce sickling. One of these, voxelotor (GBT440), is currently in advanced clinical trials. A structural analogue, GBT1118, was investigated in the current work. As RBC dehydration is important in pathogenesis of SCA, the effect of GBT1118 on RBC cation permeability was also studied. Activities of Psickle, the Gardos channel and the KCl cotransporter (KCC) were all reduced. Gardos channel and KCC activities were also inhibited in RBCs treated with Ca2+ ionophore or the thiol reagent N‐ethylmaleimide, indicative of direct effects on these two transport systems. Consistent with its action on RBC membrane transporters, GBT1118 significantly increased RBC hydration. RBC hemolysis was reduced in a nonelectrolyte lysis assay. Further to its direct effects on O2 affinity, GBT1118 was therefore found to reduce RBC shrinkage and fragility. Findings reveal important effects of GBT1118 on protecting sickle cells and suggest that this is approach may represent a useful therapy for amelioration of the clinical complications of SCA.
Databáze: OpenAIRE
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