title: Proteases essential for human influenza virus entry into cells and their inhibitors as potential therapeutic agents.
abstract: Influenza A virus (IAV) is one of the most common infectious pathogens in humans. Since IVA genome does not have the processing protease for the viral membrane fusion glycoprotein precursors, entry of this virus into cells is determined primarily by host cellular, trypsin-type, processing proteases that proteolytically activate the fusion glycoprotein precursors of IAV. At least five different processing proteases have been identified in the airways of animals and humans. These proteases determine the infectious organ tropism of IAV infection as well as the efficiency of viral multiplication in the airway, and sometimes in the brain. Proteases in the upper respiratory tract are suppressed by secretory leukoprotease inhibitor, and those in the lower respiratory tract are suppressed by pulmonary surfactant which, by adsorption, inhibits the interaction between the proteases and viral membrane proteins. Since protease activities predominate over those of endogenous inhibitory compounds under normal airway conditions, administration of protease inhibitors in the early-stage of infection significantly suppresses viral entry and viral multiplication. Several viral neuraminidase inhibitors are used clinically as anti-influenza virus agents, based on their inhibitory action on viral release from infected cells. Furthermore, protease inhibitors of viral entry could be potentially useful against influenza virus as well as neuraminidase inhibitor-resistant viruses. We also found that ambroxol, a mucolytic and anti-oxidant agent, up-regulates the levels of endogenous protease inhibitory compounds in the airway fluids in early-phase infection, and that clarithromycin, a macrolide antibiotic, increases IgA levels and mucosal immunity through augmentation of interleukin-12 levels in the airway. The combination of neuraminidase inhibitors and protease inhibitors, clarithromycin or ambroxol, could be potentially used as a potent anti-influenza therapy to minimize the emergence of drug-resistant mutant viruses.
authors.affiliation: Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Kuramoto-cho 3-18-15, Tokushima 770-8503, Japan. kido@ier.tokushima-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kido
authors.forename: Yuushi
authors.initials: Y
authors.lastname: Okumura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Trong Quang
authors.initials: TQ
authors.lastname: Le
authors.forename: Mihiro
authors.initials: M
authors.lastname: Yano
mesh_terms: D000551:Ambroxol / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism / Q000821:virology; D017291:Clarithromycin / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005100:Expectorants / Q000494:pharmacology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D007251:Influenza, Human / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational; D011663:Pulmonary Surfactants / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D005100:Expectorants; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011480:Protease Inhibitors; D011663:Pulmonary Surfactants; D053481:Secretory Leukocyte Peptidase Inhibitor; D000551:Ambroxol; D009439:Neuraminidase; D010447:Peptide Hydrolases; D017291:Clarithromycin