A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of fibrosis disease
A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of fibrosis disease
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DOI：
10.1016/j.chembiol.2022.02.001
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发表时间：
2022-06-16
影响因子：
8.6
通讯作者：
Martin, S. Lorraine
中科院分区：
文献类型：
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作者：
Douglas, Lisa E. J.;Reihill, James A.;Martin, S. Lorraine
在囊性纤维化 (CF) 中，过度的弗林蛋白酶活性在上皮钠通道 (ENaC) 的激活中起着关键作用，其失调会导致气道脱水、粘液纤毛清除无效 (MCC) 和粘液阻塞。在这里，我们报道了一种高选择性、细胞渗透性弗林蛋白酶抑制剂 BOS-318，它通过引发独立于活性位点催化三联体的新的、意想不到的结合袋的形成来获得选择性。使用人类离体模型，BOS-318 显示出对 ENaC 的显着抑制，从而增强气道水合并使 MCC 发生率增加 -30 倍。弗林蛋白酶抑制还可以保护 ENaC 免受中性粒细胞弹性蛋白酶（CF 气道中占主导地位的可溶性蛋白酶）的后续激活。其他治疗益处包括防止铜绿假单胞菌外毒素 A 诱导的上皮细胞死亡。我们的研究结果证明了选择性弗林蛋白酶抑制作为一种突变不可知方法的效用，可以以预期提供治疗价值的方式纠正 CF 气道病理生理学特征。
In cystic fibrosis (CF), excessive furin activity plays a critical role in the activation of the epithelial sodium channel (ENaC), dysregulation of which contributes to airway dehydration, ineffective mucociliary clearance (MCC), and mucus obstruction. Here, we report a highly selective, cell-permeable furin inhibitor, BOS-318, that derives selectivity by eliciting the formation of a new, unexpected binding pocket independent of the active site catalytic triad. Using human ex vivo models, BOS-318 showed significant suppression of ENaC, which led to enhanced airway hydration and an -30-fold increase in MCC rate. Furin inhibition also protected ENaC from subsequent activation by neutrophil elastase, a soluble protease dominant in CF airways. Addi-tional therapeutic benefits include protection against epithelial cell death induced by Pseudomonas aerugi-nosa exotoxin A. Our findings demonstrate the utility of selective furin inhibition as a mutation-agnostic approach that can correct features of CF airway pathophysiology in a manner expected to deliver therapeutic value.