Departamento de Química, Universidad de Burgos, Burgos, Spain.
Department of Biochemistry, University of Zurich, Zurich, Switzerland.
J Cyst Fibros. 2020 Mar;19 Suppl 1:S37-S41. doi: 10.1016/j.jcf.2019.10.020. Epub 2019 Oct 26.
Cystic fibrosis is a hereditary disease that originates from mutations in the epithelial chloride channel CFTR. Whereas established therapies for the treatment of cystic fibrosis target CFTR to repair its function, alternative therapeutic strategies aim for the restoration of chloride transport by the activation of other chloride transport proteins such as TMEM16A or SLC26A9 or by the application of synthetic anionophores. TMEM16A is an anion-selective channel that is activated by the binding of Ca from the cytoplasm. Pharmacological efforts aim for the increase of its open probability at resting Ca concentrations. SLC26 is an uncoupled chloride transporter, which shuttles chloride across the membrane by an alternate-access mechanism. Its activation requires its mobilization from intracellular stores. Finally, anionophores are small synthetic molecules that bind chloride to form lipid-soluble complexes, which shuttle the anion across the membrane. All three approaches are currently pursued and have provided promising initial results.
囊性纤维化是一种遗传性疾病，源于上皮氯离子通道 CFTR 的突变。虽然用于治疗囊性纤维化的既定疗法针对 CFTR 以修复其功能，但替代治疗策略旨在通过激活其他氯离子转运蛋白（如 TMEM16A 或 SLC26A9）或应用合成阴离子载体来恢复氯离子转运。TMEM16A 是一种阴离子选择性通道，其通过细胞质中的 Ca 结合而被激活。药理学努力旨在增加其在静息 Ca 浓度下的开放概率。SLC26 是一种不偶联的氯离子转运体，通过交替访问机制将氯离子穿梭穿过膜。其激活需要从细胞内储存库中动员。最后，阴离子载体是小的合成分子，它们与氯离子结合形成亲脂性复合物，将阴离子穿梭穿过膜。所有这三种方法目前都在研究中，并提供了有希望的初步结果。
