JBC：FDA批准新药VX-770用于囊性纤维化

近日，多伦多科学家证实FDA最近批准的治疗一种罕见囊性纤维化的药物可能治疗各种形式的囊肿性纤维化。

囊性纤维化是一种遗传性疾病，困扰着世界各地的约70000人。患者的上皮细胞氯离子通道调节有缺陷；呼吸道粘膜上皮的水、电解质跨膜转运有障碍；粘液腺分泌物中酸性糖蛋白含量增加，改变了粘液流变学的特性，可能为分泌物变粘稠的原因。

当该传输过程被中断后，某些器官的粘液粘度会变得过厚。而疾病的一个主要特征是厚厚的黏液积聚在空气通道中导致呼吸困难，引发反复感染。虽然FDA批准的药物VX-770可以缓解特定基因CFTR突变导致的囊肿性纤维化患者的呼吸，但VX-770究竟是如何发挥作用的仍不是很清楚。

当前，科学家们已经了解到正常的CFTR发挥作用需要经过蛋白质修改过程，结合到能源小分子三磷酸腺苷或ATP上。但这项发表在Journal of Biological Chemistry杂志上的新研究证实在ATP不存在情况下，药物VX-770能打开正常和突变的CFTR通道。他们的研究结果表明，该药物是结合CTFR上的不同位点，而不是ATP。

值得注意的是，这一发现可能有助于开发治疗CFTR突变所造成的囊肿性纤维化新的药物。Bear研究小组开发了一个新的实验系统用于发现靶向CFTR基因突变缺陷的药物。

doi:10.1074/jbc.M112.393637
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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Potentiator VX-770 (Ivacaftor) Opens the Defective Channel Gate of Mutant CFTR in a Phosphorylation-dependent but ATP-independent Manner

Paul D. W. Eckford1, Canhui Li, Mohabir Ramjeesingh and Christine E. Bear

The cystic fibrosis transmembrane conductance regulator (CFTR) acts as a channel on the apical membrane of epithelia. Disease-causing mutations in the cystic fibrosis gene can lead to CFTR protein misfolding as in the case of the F508del mutation and/or channel dysfunction. Recently, a small molecule, VX-770 (ivacaftor), has shown efficacy in restoring lung function in patients bearing the G551D mutation, and this has been linked to repair of its channel gating defect. However, these studies did not reveal the mechanism of action of VX-770 in detail. Normally, CFTR channel activity is regulated by phosphorylation, ATP binding, and hydrolysis. Hence, it has been hypothesized that VX-770 modifies one or more of these metabolic events. In this study, we examined VX-770 activity using a reconstitution system for purified CFTR protein, a system that enables control of known regulatory factors. We studied the consequences of VX-770 interaction with CFTR incorporated in planar lipid bilayers and in proteoliposomes, using a novel flux-based assay. We found that purified and phosphorylated CFTR was potentiated in the presence of Mg-ATP, suggesting that VX-770 bound directly to the CFTR protein, rather than associated kinases or phosphatases. Interestingly, we also found that VX-770 enhanced the channel activity of purified and mutant CFTR in the nominal absence of Mg-ATP. These findings suggest that VX-770 can cause CFTR channel opening through a nonconventional ATP-independent mechanism. This work sets the stage for future studies of the structural properties that mediate CFTR gating using VX-770 as a probe.