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J Med Chem. 2014 Jan 9;57(1):29-41. doi: 10.1021/jm400633d. Epub 2013 Dec 23.

Optimization of furin inhibitors to protect against the activation of influenza hemagglutinin H5 and Shiga toxin.

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Institut de Pharmacologie de Sherbrooke (IPS) and Département de Chirurgie/Urologie, Faculté de Médecine et des Sciences de la Santé (FMSS), Université de Sherbrooke , 3001, 12e Avenue Nord, Sherbrooke, Québec J1H 5N4, Canada.


Proprotein convertases (PCs) are crucial in the processing and entry of viral or bacterial protein precursors and confer increased infectivity of pathogens bearing a PC activation site, which results in increased symptom severity and lethality. Previously, we developed a nanomolar peptide inhibitor of PCs to prevent PC activation of infectious agents. Herein, we describe a peptidomimetic approach that increases the stability of this inhibitor for use in vivo to prevent systemic infections and cellular damage, such as that caused by influenza H5N1 and Shiga toxin. The addition of azaβ(3)-amino acids to both termini of the peptide successfully prevented influenza hemagglutinin 5 fusogenicity and Shiga toxin Vero toxicity in cell-based assays. The results from a cell-based model using stable shRNA-induced proprotein convertase knockdown indicate that only furin is the major proprotein convertase required for HA5 cleavage.

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