Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas,FEBS Letters

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Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas
FEBS Letters ( IF 3.0 ) Pub Date : 2020-11-16 , DOI: 10.1002/1873-3468.13971
Hugo R de Jonge ₁ , Maria C Ardelean _{2,

3} , Marcel J C Bijvelds ₁ , Paola Vergani ₂

Affiliation

Cystic fibrosis transmembrane conductance regulator (CFTR) is an unusual ABC transporter. It acts as an anion‐selective channel that drives osmotic fluid transport across many epithelia. In the gut, CFTR is crucial for maintaining fluid and acid‐base homeostasis, and its activity is tightly controlled by multiple neuro‐endocrine factors. However, microbial toxins can disrupt this intricate control mechanism and trigger protracted activation of CFTR. This results in the massive faecal water loss, metabolic acidosis and dehydration that characterize secretory diarrhoeas, a major cause of malnutrition and death of children under 5 years of age. Compounds that inhibit CFTR could improve emergency treatment of diarrhoeal disease. Drawing on recent structural and functional insight, we discuss how existing CFTR inhibitors function at the molecular and cellular level. We compare their mechanisms of action to those of inhibitors of related ABC transporters, revealing some unexpected features of drug action on CFTR. Although challenges remain, especially relating to the practical effectiveness of currently available CFTR inhibitors, we discuss how recent technological advances might help develop therapies to better address this important global health need.

中文翻译：

囊性纤维化跨膜电导调节器抑制策略：从分子机制到分泌性腹泻的治疗

囊性纤维化跨膜电导调节剂 (CFTR) 是一种不常见的 ABC 转运蛋白。它作为一种阴离子选择性通道，驱动渗透液在许多上皮细胞中的转运。在肠道中，CFTR 对维持体液和酸碱平衡至关重要，其活性受到多种神经内分泌因子的严格控制。然而，微生物毒素可以破坏这种复杂的控制机制并引发 CFTR 的长期激活。这导致大量粪便失水、代谢性酸中毒和脱水，这是分泌性腹泻的特征，这是 5 岁以下儿童营养不良和死亡的主要原因。抑制 CFTR 的化合物可以改善腹泻病的紧急治疗。借鉴最近的结构和功能洞察力，我们讨论了现有的 CFTR 抑制剂如何在分子和细胞水平上发挥作用。我们将它们的作用机制与相关 ABC 转运蛋白抑制剂的作用机制进行了比较，揭示了药物对 CFTR 作用的一些意想不到的特征。尽管挑战依然存在，特别是与目前可用的 CFTR 抑制剂的实际有效性有关，但我们讨论了最近的技术进步如何帮助开发治疗方法，以更好地满足这一重要的全球健康需求。

更新日期：2020-11-16

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