Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors

• DOI: 10.1038/ncomms7722
• Publication Date: 2015-04-10T10:49:23Z
• Authors: T. Dau; R. S. J. Sarker; A. O. Yildirim; O. Eickelberg; D. E. Jenne
• Keywords: Neutrophil elastase

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 neutrophil elastase have failed in clinic. Here we discover intrinsic self-cleaving property of mouse that interferes with action inhibitors. We show conversion single-chain (sc) into a two-chain (tc) by self-cleavage near its S1 pocket altered substrate activity impaired both inhibition endogenous α-1-antitrypsin synthetic small molecules. Our data indicate autoconversion decreases inhibitory efficacy natural inhibitors, while retaining pathological potential experimental model. The so-far overlooked occurrence properties naturally occurring tc-form necessitates redesign target sc-form well elastase. Elastase secreted immune cells contributes various diseases; however, mostly Here, authors second, truncated form elastase, which result autocatalytic cleavage not targeted current