Department of Physiology and Pharmacology, University of Bristol, School of Medical Sciences, Bristol, UK.
BioDrugs. 2009;23(4):203-16. doi: 10.2165/11313570-000000000-00000.
In the common genetic disorder autosomal dominant polycystic kidney disease (ADPKD), kidney function is disrupted by multiple fluid-filled epithelial cysts. Cyst growth in ADPKD involves fluid accumulation within the cyst lumen driven by cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial Cl- secretion. This suggests that inhibitors of the CFTR Cl- channel might retard cyst growth. This review considers how knowledge of CFTR structure and function and its role in transepithelial salt and water movements provides insight into the mechanism of action of CFTR inhibitors. Some small molecules, termed open-channel blockers, inhibit directly the CFTR Cl- channel by physically obstructing the CFTR pore and preventing Cl- flow. By contrast, other small molecules, termed allosteric inhibitors, bind to CFTR at a site remote from the channel pore and interfere with conformational changes that open the pore. The application of high-throughput screening to CFTR drug discovery has led to the identification of new inhibitors of the CFTR Cl- channel including the thiazolidinone CFTR(inh)-172 and the glycine hydrazide GlyH-101. The demonstration that CFTR inhibitors retard cyst expansion and kidney enlargement in mouse models of ADPKD provides proof of concept for the use of small-molecule CFTR inhibitors in the treatment of ADPKD.
在常见的常染色体显性多囊肾病（ADPKD）遗传疾病中，肾脏功能被多个充满液体的上皮囊肿破坏。ADPKD 中的囊肿生长涉及由囊性纤维化跨膜电导调节因子（CFTR）介导的跨上皮 Cl-分泌引起的囊肿腔中的液体积累。这表明 CFTR Cl-通道的抑制剂可能会减缓囊肿生长。这篇综述考虑了 CFTR 结构和功能及其在跨上皮盐和水运动中的作用如何为 CFTR 抑制剂的作用机制提供了深入的了解。一些小分子，称为开放通道阻滞剂，通过物理阻塞 CFTR 孔并阻止 Cl-流动，直接抑制 CFTR Cl-通道。相比之下，其他小分子，称为别构抑制剂，在远离通道孔的 CFTR 上结合，并干扰打开孔的构象变化。高通量筛选在 CFTR 药物发现中的应用导致了 CFTR Cl-通道的新抑制剂的鉴定，包括噻唑烷二酮 CFTR(inh)-172 和甘氨酸酰肼 GlyH-101。CFTR 抑制剂可减缓 ADPKD 小鼠模型中囊肿扩张和肾脏增大的证明为使用小分子 CFTR 抑制剂治疗 ADPKD 提供了概念验证。
