Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs
Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs
复制标题
DOI：
10.1039/c9sc04242c
复制
发表时间：
2019-11-14
期刊：
影响因子：
8.4
通讯作者：
Davis, Anthony P.
中科院分区：
文献类型：
--
作者：
Li, Hongyu;Valkenier, Hennie;Davis, Anthony P.
阴离子运输缺陷是遗传性疾病囊性纤维化（CF）的标志。一种恢复阴离子转运到CF细胞的方法是利用可选的跨膜阴离子转运途径，包括人工阴离子载体（阴离子载体）。在这里，我们利用卤素敏感黄色荧光蛋白的荧光发射筛选了22个阴离子载体的生物活性。有三种化合物具有与双（对硝基苯）脲十烷相似或更高的阴离子转运活性，这些化合物先前已被证明具有很好的生物活性。这些阴离子载体的阴离子转运具有浓度依赖性和持久性。这四种阴离子载体都介导了CF细胞中的阴离子运输，它们的活性有助于使用临床许可的药物lumacaftor和ivacaftor拯救主要致病变异F508del-CFTR。毒性是可变的，但在较低的一端最小。结果进一步证明，阴离子载体本身或与其他恢复阴离子运输的治疗方法一起，为CF提供了一种潜在的治疗策略。
Defective anion transport is a hallmark of the genetic disease cystic fibrosis (CF). One approach to restore anion transport to CF cells utilises alternative pathways for transmembrane anion transport, including artificial anion carriers (anionophores). Here, we screened 22 anionophores for biological activity using fluorescence emission from the halide-sensitive yellow fluorescent protein. Three compounds possessed anion transport activity similar to or greater than that of a bis-(p-nitrophenyl)ureidodecalin previously shown to have promising biological activity. Anion transport by these anionophores was concentration-dependent and persistent. All four anionophores mediated anion transport in CF cells, and their activity was additive to rescue of the predominant disease-causing variant F508del-CFTR using the clinically-licensed drugs lumacaftor and ivacaftor. Toxicity was variable but minimal at the lower end. The results provide further evidence that anionophores, by themselves or together with other treatments that restore anion transport, offer a potential therapeutic strategy for CF.