Al Balushi Halima, Dufu Kobina, Rees David C, Brewin John N, Hannemann Anke, Oksenberg Donna, Lu David C-Y, Gibson John S
Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
Global Blood Therapeutics, South San Francisco, California.
Physiol Rep. 2019 Mar;7(6):e14027. doi: 10.14814/phy2.14027.
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 ) 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 P , the Gardos channel and the KCl cotransporter (KCC) were all reduced. Gardos channel and KCC activities were also inhibited in RBCs treated with Ca 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 O 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.
镰状细胞贫血（SCA）是最常见的严重遗传性疾病之一。然而，有效的治疗方法仍然不足，人们迫切寻求新的治疗方法。一个有前景的进展是设计出与血红蛋白S（HbS）反应以增加氧（O）亲和力并减少镰变的新型化合物。其中一种化合物，voxelotor（GBT440），目前正处于晚期临床试验阶段。在当前的研究中对其结构类似物GBT1118进行了研究。由于红细胞脱水在SCA的发病机制中很重要，因此还研究了GBT1118对红细胞阳离子通透性的影响。P、加尔多斯通道和氯化钾协同转运蛋白（KCC）的活性均降低。在用钙离子载体或硫醇试剂N - 乙基马来酰亚胺处理的红细胞中，加尔多斯通道和KCC的活性也受到抑制，这表明对这两种转运系统有直接影响。与其对红细胞膜转运蛋白的作用一致，GBT1118显著增加了红细胞的水合作用。在非电解质裂解试验中，红细胞溶血减少。除了对氧亲和力的直接影响外，因此发现GBT1118还能减少红细胞的收缩和脆性。研究结果揭示了GBT1118在保护镰状细胞方面的重要作用，并表明这种方法可能是改善SCA临床并发症的一种有效治疗方法。
