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

Journal of Medicinal Chemistry
Hugo GagnonRobert Day

Abstract

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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Citations

Sep 14, 2015·Current Opinion in Virology·Tokiko Watanabe, Yoshihiro Kawaoka
Apr 23, 2015·Journal of Biomolecular Structure & Dynamics·Olaposi I Omotuyi, Tsuyoshi Hamada
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Oct 24, 2017·ChemMedChem·Teodora IvanovaTorsten Steinmetzer
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Aug 25, 2020·SN Comprehensive Clinical Medicine·Yi Ming, Liu Qiang
Mar 19, 2021·ACS Medicinal Chemistry Letters·Thuy Van Lam vanTorsten Steinmetzer
Mar 20, 2021·ACS Medicinal Chemistry Letters·Monika A Lewandowska-GochRobert Day
Aug 4, 2021·Journal of Medicinal Chemistry·Essam Eldin A OsmanNouri Neamati

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