oxadiazoles and Influenza--Human

Topics: Acetamides; Amines; Antiviral Agents; Common Cold; Guanidines; Humans; Influenza, Human; Intercellular Adhesion Molecule-1; Neuraminidase; Oseltamivir; Oxadiazoles; Oxazoles; Picornaviridae Infections; Pyrans; Recombinant Proteins; Rhinovirus; Sialic Acids; Zanamivir

Neuraminidase (NA) is a prominent surface antigen of Influenza viruses, which helps in release of viruses from the host cells after replication. Anti influenza drugs such as Oseltamivir target a highly conserved active site of NA, which comprises of 8 functional residues (R118, D151, R152, R224, E276, R292, R371 and Y406) to restrict viral release from host cells, thus inhibiting its ability to cleave sialic acid residues on the cell membrane. Reports on the emergence of Oseltamivir resistant strains of H1N1 Influenza virus necessitated a search for alternative drug candidates. Pleconaril is a novel antiviral drug being developed by Schering-Plough to treat Picornaviridae infections, and is in its late clinical trials stage. Since, Pleconaril was designed to bind the highly conserved hydrophobic binding site on VP1 protein of Picorna viruses, the ability of Pleconaril and its novel substituted derivatives to bind highly conserved hydrophobic active site of H1N1 Neuraminidase, targeting which oseltamivir has been designed was investigated.. 310 novel substituted variants of Pleconaril were designed using Chemsketch software and docked into the highly conserved active site of NA using arguslab software. 198 out of 310 Pleconaril variants analyzed for docking with NA active site were proven effective, based on their free binding energy.. Pleconaril variants with F, Cl, Br, CH3, OH and aromatic ring substitutions were shown to be effective alternatives to Oseltamivir as anti influenza drugs.

Topics: Amino Acids; Antiviral Agents; Binding Sites; Biocatalysis; Catalytic Domain; Drug Evaluation, Preclinical; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Hydrogen Bonding; Influenza A Virus, H1N1 Subtype; Influenza, Human; Models, Molecular; Molecular Structure; Neuraminidase; Oseltamivir; Oxadiazoles; Oxazoles; Protein Binding; Protein Structure, Tertiary

Topics: Antiviral Agents; Common Cold; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Oxadiazoles; Oxazoles; Rhinovirus; Viral Structural Proteins; Viral Vaccines

NEURAMINIDASE INHIBITORS: Zanamivir, the leading neuraminidase inhibitor has been awarded marketing approval in France for curative treatment of flu. It has been demonstrated that zanamivir reduces the duration of symptoms and the frequency of recourse to antibiotics. INDICATIONS FOR ZANAMIVIR: Besides early prescription for curative treatment of flu, as soon as the first symptoms occur, particularly in vaccinated elderly patients (vaccination is effective in only 70 to 80% of cases), zanamivir could also be used as a preventive treatment in subjects exposed to an index case. EARLY TRIALS WITH PLECONARIL: Pleconaril is active against picomaviruses and appears to have interesting efficacy against exceptionally severe enterovirus infections. Conversely, trials conducted in cases of upper respiratory tract infections and meningitis caused by enteroviruses have shown modest results.

Topics: Antiviral Agents; Drug Approval; France; Guanidines; Humans; Influenza, Human; Neuraminidase; Oxadiazoles; Oxazoles; Picornaviridae Infections; Pyrans; Respiratory Tract Infections; Sialic Acids; Zanamivir

Topics: Antitussive Agents; Bronchial Diseases; Bronchitis; Bronchopneumonia; Hemopneumothorax; Humans; Influenza, Human; Lung Diseases; Oxadiazoles; Pleurisy; Pneumonia; Pneumonia, Viral; Respiratory Tract Infections; Tetracycline