The effect of the antisickling compound GBT 1118 on the permeability of red blood cells from patients with sickle cell anemia

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 .