Li Hongyu, Valkenier Hennie, Thorne Abigail G, Dias Christopher M, Cooper James A, Kieffer Marion, Busschaert Nathalie, Gale Philip A, Sheppard David N, Davis Anthony P
School of Physiology , Pharmacology and Neuroscience , University of Bristol , Biomedical Sciences Building, University Walk , Bristol BS8 1TD , UK . Email:
School of Chemistry , University of Bristol , Cantock's Close , Bristol BS8 1TS , UK . Email:
Chem Sci. 2019 Oct 2;10(42):9663-9672. doi: 10.1039/c9sc04242c. eCollection 2019 Nov 14.
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-(-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.
阴离子转运缺陷是遗传性疾病囊性纤维化（CF）的一个标志。恢复CF细胞阴离子转运的一种方法是利用跨膜阴离子转运的替代途径，包括人工阴离子载体（离子载体）。在这里，我们使用卤化物敏感型黄色荧光蛋白的荧光发射筛选了22种离子载体的生物活性。三种化合物具有与先前显示具有良好生物活性的双（-硝基苯基）脲基十氢化萘相似或更高的阴离子转运活性。这些离子载体介导的阴离子转运具有浓度依赖性且持续存在。所有四种离子载体在CF细胞中均介导阴离子转运，并且它们的活性与使用临床许可药物鲁马卡托和依伐卡托挽救主要致病变体F508del-CFTR的活性相加。毒性各不相同，但在较低剂量时最小。结果提供了进一步的证据，表明离子载体本身或与恢复阴离子转运的其他治疗方法一起，为CF提供了一种潜在的治疗策略。
