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首页> 外文期刊>Nature Communications >Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors
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Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors

机译：中性粒细胞弹性蛋白酶在其活性位点附近的自动加工降低了天然和合成弹性蛋白酶抑制剂的效率

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An imbalance between neutrophil-derived proteases and extracellular inhibitors is widely regarded as an important pathogenic mechanism for lung injury. Despite intense efforts over the last three decades, attempts to develop small-molecule inhibitors for neutrophil elastase have failed in the clinic. Here we discover an intrinsic self-cleaving property of mouse neutrophil elastase that interferes with the action of elastase inhibitors. We show that conversion of the single-chain (sc) into a two-chain (tc) neutrophil elastase by self-cleavage near its S1 pocket altered substrate activity and impaired both inhibition by endogenous α-1-antitrypsin and synthetic small molecules. Our data indicate that autoconversion of neutrophil elastase decreases the inhibitory efficacy of natural α-1-antitrypsin and small-molecule inhibitors, while retaining its pathological potential in an experimental mouse model. The so-far overlooked occurrence and properties of a naturally occurring tc-form of neutrophil elastase necessitates the redesign of small-molecule inhibitors that target the sc-form as well as the tc-form of neutrophil elastase.
机译：中性粒细胞衍生的蛋白酶和细胞外抑制剂之间的失衡被广泛认为是肺损伤的重要致病机制。尽管在过去的三十年中付出了巨大的努力，但在临床上仍未能开发出用于中性粒细胞弹性蛋白酶的小分子抑制剂。在这里，我们发现了小鼠嗜中性粒细胞弹性蛋白酶的内在自我裂解特性，干扰了弹性蛋白酶抑制剂的作用。我们显示单链（sc）转化为两链（tc）中性粒细胞弹性蛋白酶通过其S1口袋附近的自我切割改变了底物活性，并削弱了内源性α-1-抗胰蛋白酶和合成小分子的抑制作用。我们的数据表明，嗜中性粒细胞弹性蛋白酶的自动转化降低了天然α-1-抗胰蛋白酶和小分子抑制剂的抑制效果，同时在实验小鼠模型中保留了其病理学潜力。迄今为止，天然存在的嗜中性粒细胞弹性蛋白酶的tc形式的被忽略和性质使得必须重新设计靶向嗜中性粒细胞弹性蛋白酶的sc形式以及tc形式的小分子抑制剂。

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