Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas.
Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas.
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DOI：
10.1002/1873-3468.13971
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发表时间：
2020-12
期刊：
影响因子：
3.5
通讯作者：
Vergani P
中科院分区：
文献类型：
--
作者：
de Jonge HR;Ardelean MC;Bijvelds MJC;Vergani P
囊性纤维化跨膜传导调节因子（CFTR）是一种不常见的ABC转运蛋白。它作为阴离子选择性通道，驱动渗透液转运穿过许多上皮细胞。在肠道中，CFTR对于维持液体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，是5岁以下儿童营养不良和死亡的主要原因。抑制CFTR的化合物可以改善肾脏疾病的紧急治疗。借鉴最近的结构和功能的见解，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。我们比较了它们的作用机制，相关的ABC转运蛋白的抑制剂，揭示了一些意想不到的特点，药物对CFTR的作用。尽管挑战仍然存在，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。
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.
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影响因子：
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作者：
Binder, Henry J;Brown, Ian;Ramakrishna, B S;Young, Graeme P
通讯作者：
Young, Graeme P
DOI：
10.1085/jgp.201411347
发表时间：
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期刊：
The Journal of general physiology
影响因子：
--
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通讯作者：
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