The influenza A virus represents one of the greatest global human health risks. While vaccines provide significant protection from seasonal flu infections they still account for an estimated 36,000 deaths and 200,000 hospitalizations per year in the US alone. Furthermore, the inherent time involved in development, production and distribution of vaccines limits their potential efficacy against rapidly emerging outbreaks. Two classes of drugs have been approved for influenza prophylaxis and treatment. Alarmingly, the past decade has witnessed the emergence of drug resistant as well as novel 2009 pandemic (H1N1) and highly pathogenic (H5N1) strains of influenza A. Amantadine- resistance has become so widespread the amantadanes have become all but ineffective and some flu strains have already exhibited significant resistance to neuraminidase inhibitors. Optimally, as adopted for the treatment of other viral diseases, combination drug therapies would be used to provide the most effective prophylaxis and treatment and to inhibit the emergence of additional drug- resistances. Thus, there is an urgent need for new and more effective antiviral mono- and combination therapies. Here we provide an innovative approach to identify inhibitors of both amantadine-sensitive and -resistant forms of the M2 proton channel to provide novel broad-spectrum therapeutics. Using this approach we provide a platform for the identification of new inhibitory compounds acting at novel sites of a clinically validated influenza A target for the development of new mono- and combination antiviral drug therapies;a designated NIAID high priority area of interest.
Public Health Relevance: Over the past decade the emergence of a number of drug-resistant and/or highly pathogenic variants of influenza have dramatically increased the potential impact of influenza infection. This proposal details an innovative approach to identify much needed novel inhibitors and potential therapeutics for the prevention and treatment of influenza A infection for mono and combination drug therapies.
Thesaurus Terms: 1-Aminoadamantane;4-Acetamido-5-Amino-3-(1-Ethylpropoxy)-1-Cyclohexene-1-Carboxylic Acid;Accounting;Adamantylamine;Adopted;Amantadine;Amantadine Resistance;Amantadine Resistant;Antiviral Agents;Antiviral Drugs;Antivirals;Area;Assay;Binding Sites;Bioassay;Biologic Assays;Biological Assay;Cell Line;Cell Lines, Strains;Cell-Mediated Cytolysis;Cell-Mediated Lympholysis;Cellline;Cells;Cellular Cytotoxicity;Cessation Of Life;Collection;Combination Drug Therapy;Combined Modality Therapy;Combining Site;Complement;Complement Proteins;Cytotoxicity, Immunologic;Data;Death;Dependence;Development;Disease Outbreaks;Drug Design;Drug Therapy;Drug Resistance;Drugs;Epidemic;Exhibits;Fluorescence Agents;Fluorescent Agents;Fluorescent Dyes;Genetic Alteration;Genetic Change;Genetic Defect;Grippe;H+ Element;H1n1 Virus;H5n1;H5n1 Virus;Hosp;Health;Hospitalization;Human;Human, General;Hydrogen Ions;Ic50;Individual;Infection;Influenza;Influenza A Virus, H1n1 Subtype;Influenza A Virus, H5n1 Subtype;Influenza A Virus;Influenza Viruses Type A;Inhibitory Concentration 50;Libraries;Lymphocyte Cytotoxicity;Lymphocytotoxicity;Lytotoxicity;Man (Taxonomy);Man, Modern;Medication;Methods;Mono-S;Monos;Multimodal Therapy;Multimodal Treatment;Multimodality Treatment;Mutation;Niaid;National Institute Of Allergy And Infectious Disease;Neuraminidase Inhibitor;Orthomyxovirus Type A;Oseltamivir;Outbreaks;Pharmaceutic Preparations;Pharmaceutical Preparations;Pharmacotherapy;Polychemotherapy;Prevention;Prevention Measures;Production;Property;Property, Loinc Axis 2;Prophylactic Treatment;Prophylaxis;Protons;Reactive Site;Reporting;Research;Resistance;Risk;Sampling;Seasons;Series;Site;Tamiflu;Testing;Tet;Tetanus Helper Peptide;Therapeutic;Time;Toxic Effect;Toxicities;Tricyclo(3.3.1.13,7)Decan-1-Amine;Vaccination;Vaccines;Validation;Variant;Variation;Viral;Viral Diseases;Virus Diseases;Anti-Flu Drug;Anti-Influenza Drug;Antiflu Drug;Base;Cell Mediated Cytotoxicity;Combat;Combination Pharmacotherapy;Combination Therapy;Combinatorial;Combined Modality Treatment;Combined Treatment;Comparative;Computational Studies;Computer Studies;Cultured Cell Line;Cytotoxicity;Drug /Agent;Drug Resistant;Drug/Agent;Flu;Flu Infection;Flu Outbreak;Fluorescent Dye /Probe;Fluorescent Dye/Probe;Genome Mutation;Influenza Infection;Influenza Outbreak;Inhibitor;Inhibitor /Antagonist;Inhibitor/Antagonist;Innovate;Innovation;Innovative;Interest;Lead Series;Library;Multimodality Therapy;Novel;Pandemic;Pandemic Disease;Pandemic Flu;Pandemic Influenza;Phase 2 Study;Resistance To Drug;Resistance To Amantadine;Resistant;Resistant Strain;Resistant To Drug;Resistant To Amantadine;Response;Scaffold;Scaffolding;Seasonal Influenza;Small Molecule;Small Molecule Libraries;Viral Infection;Virus Infection
