title: Optimization of furin inhibitors to protect against the activation of influenza hemagglutinin H5 and Shiga toxin.
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.
authors.affiliation: 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.
authors.forename: Hugo
authors.initials: H
authors.lastname: Gagnon
authors.forename: Sophie
authors.initials: S
authors.lastname: Beauchemin
authors.forename: Anna
authors.initials: A
authors.lastname: Kwiatkowska
authors.forename: Frédéric
authors.initials: F
authors.lastname: Couture
authors.forename: François
authors.initials: F
authors.lastname: D'Anjou
authors.forename: Christine
authors.initials: C
authors.lastname: Levesque
authors.forename: Frédérik
authors.initials: F
authors.lastname: Dufour
authors.forename: Adamy Roberge
authors.initials: AR
authors.lastname: Desbiens
authors.forename: Rolland
authors.initials: R
authors.lastname: Vaillancourt
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bernard
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.forename: François
authors.initials: F
authors.lastname: Malouin
authors.forename: Yves L
authors.initials: YL
authors.lastname: Dory
authors.forename: Robert
authors.initials: R
authors.lastname: Day
mesh_terms: D045683:Furin / Q000037:antagonists & inhibitors* / Q000502:physiology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D057786:Peptidomimetics; D022621:Shiga Toxin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D057786:Peptidomimetics; C109963:hemagglutinin, avian influenza A virus; D022621:Shiga Toxin; D045683:Furin