title: Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics.
abstract: Cellular proteases are reponsible for activation of influenza virus hemagglutinin (HA) in epithelial tissues of the respiratory tract. The trans-Golgi network (TGN) is the main subcellular compartment where HA cleavage occurs during its biosynthesis. The proteolytic HA cleavage is an indispensable prerequisite for the fusion of viral with endosomal membrane and the delivery of the virus genome into the cell. Both, the structure and accessibility of the HA cleavage site determine the responsible host protease(s) for cutting. Most influenza virus strains contain a HA sequence with a single arginine at the cleavage site suitable for processing by the trypsin-like serine proteases human airway trypsin-like protease (HAT) and transmembrane protease serine 2 (TMPRSS2), albeit a minority of viruses possesses HA cleavage site motifs that are processed by other proteases. TMPRSS2-deficient mice demonstrated the relevance of TMPRSS2 for pneumotropism and pathogenicity of H1N1 and H7N9 virus infections. In contrast, H3N2 virus infections are promoted by an additional not yet identified protease. Highly pathogenic avian H5 and H7 viruses are characterized by an enlarged cleavage site loop containing a multibasic amino acid motif, where the eukaryotic subtilases furin or PC5/6 cleave. Their ubiquitous presence in the organism allows a systemic virus infection. Peptidomimetic inhibitors derived from the HA cleavage site inhibit the HA-activating proteases and thus virus propagation.
authors.affiliation: Institute of Virology, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany. Electronic address: garten@staff.uni-marburg.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Garten
authors.affiliation: Institute of Virology, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Braden
authors.affiliation: Institute of Virology, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Arendt
authors.affiliation: Institute of Virology, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Peitsch
authors.affiliation: Institute of Virology, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Baron
authors.affiliation: Institute of Virology, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Institute of Virology, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Pawletko
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6-10, 35032 Marburg, Germany.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hardes
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6-10, 35032 Marburg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.affiliation: Institute of Virology, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Böttcher-Friebertshäuser
mesh_terms: D000818:Animals; D045683:Furin / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D053122:Influenza A Virus, H3N2 Subtype / Q000472:pathogenicity; D064766:Influenza A Virus, H7N9 Subtype / Q000472:pathogenicity*; D007251:Influenza, Human / Q000473:pathology / Q000821:virology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000473:pathology / Q000821:virology; D045702:Proprotein Convertase 5 / Q000378:metabolism; D020545:Respiratory Mucosa / Q000821:virology; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D057057:Serine Proteases / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D057057:Serine Proteases; D045702:Proprotein Convertase 5; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; C000588699:TMPRSS2 protein, mouse; C112256:human airway trypsin-like protease; D045683:Furin
keywords: Cellular host proteases; Compartimentalization of proteases; Protease inhibitors as antivirals; Proteolytic activation of influenza viruses