Open AccessThe effect of the antisickling compound GBT 1118 on the permeability of red blood cells from patients with sickle cell anemia
Author(s) -
Al Balushi Halima,
Dufu Kobina,
Rees David C.,
Brewin John N.,
Hannemann Anke,
Oksenberg Donna,
Lu David C.Y.,
Gibson John S.
Publication year - 2019
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.14027
Subject(s) - hemolysis , red blood cell , erythrocyte fragility , anemia , hemoglobin , chemistry , pharmacology , sickle cell anemia , hemolytic anemia , membrane permeability , medicine , cell , biochemistry , immunology , membrane
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 (O 2 ) affinity and reduce sickling. One of these, voxelotor ( GBT 440), is currently in advanced clinical trials. A structural analogue, GBT 1118, was investigated in the current work. As RBC dehydration is important in pathogenesis of SCA , the effect of GBT 1118 on RBC cation permeability was also studied. Activities of P sickle , the Gardos channel and the KC l cotransporter ( KCC ) were all reduced. Gardos channel and KCC activities were also inhibited in RBC s treated with Ca 2+ ionophore or the thiol reagent N ‐ethylmaleimide, indicative of direct effects on these two transport systems. Consistent with its action on RBC membrane transporters, GBT 1118 significantly increased RBC hydration. RBC hemolysis was reduced in a nonelectrolyte lysis assay. Further to its direct effects on O 2 affinity, GBT 1118 was therefore found to reduce RBC shrinkage and fragility. Findings reveal important effects of GBT 1118 on protecting sickle cells and suggest that this is approach may represent a useful therapy for amelioration of the clinical complications of SCA .