title: NADPH oxidases as novel pharmacologic targets against influenza A virus infection.
abstract: Influenza A viruses represent a major global health care challenge, with imminent pandemics, emerging antiviral resistance, and long lag times for vaccine development, raising a pressing need for novel pharmacologic strategies that ideally target the pathology irrespective of the infecting strain. Reactive oxygen species (ROS) pervade all facets of cell biology with both detrimental and protective properties. Indeed, there is compelling evidence that activation of the NADPH oxidase 2 (NOX2) isoform of the NADPH oxidase family of ROS-producing enzymes promotes lung oxidative stress, inflammation, injury, and dysfunction resulting from influenza A viruses of low to high pathogenicity, as well as impeding virus clearance. By contrast, the dual oxidase isoforms produce ROS that provide vital protective antiviral effects for the host. In this review, we propose that inhibitors of NOX2 are better alternatives than broad-spectrum antioxidant approaches for treatment of influenza pathologies, for which clinical efficacy may have been limited owing to poor bioavailability and inadvertent removal of beneficial ROS. Finally, we briefly describe the current suite of NADPH oxidase inhibitors and the molecular features of the NADPH oxidase enzymes that could be exploited by drug discovery for development of more specific and novel inhibitors to prevent or treat disease caused by influenza.
authors.affiliation: Respiratory Research Group, Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne (R.V.), and Oxidant and Inflammation Biology Group, Department of Pharmacology, Monash University (S.S.), Victoria, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.affiliation: Respiratory Research Group, Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne (R.V.), and Oxidant and Inflammation Biology Group, Department of Pharmacology, Monash University (S.S.), Victoria, Australia Stavros.selemidis@monash.edu.
authors.forename: Stavros
authors.initials: S
authors.lastname: Selemidis
mesh_terms: D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009980:Influenza A virus / Q000201:enzymology*; D007251:Influenza, Human / Q000188:drug therapy*; D016676:Macrophages, Alveolar / Q000201:enzymology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D008563:Membrane Lipids / Q000737:chemistry; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D010743:Phospholipids / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D008563:Membrane Lipids; D010743:Phospholipids; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases