α_1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: Application as an antipathogenic agent

摘要

The important role of furin in the proteolytic activation of many pathogenic molecules has made this endo- protease a target for the development of potent and selective antiproteolytic agents. Here, we demonstrate the utility of the protein-based inhibitor α_1-antitrypsin Portland (α_1-PDX) as an antipathogenic agent that can be used prophylactically to block furin-dependent cell killing by Pseudomonas exotoxin A. Bio- chemical analysis of the specificity of a bacterially expressed His- and FLAG-tagged α_1-PDX (α_1-PDX/hf) revealed the selectivity of the α_1-PDX/hf reactive site loop for furin (Ki, 600 pM) but not for other proprotein convertase family members or other unre- lated endoproteases.