title: Aureonitol, a Fungi-Derived Tetrahydrofuran, Inhibits Influenza Replication by Targeting Its Surface Glycoprotein Hemagglutinin.
abstract: The influenza virus causes acute respiratory infections, leading to high morbidity and mortality in groups of patients at higher risk. Antiviral drugs represent the first line of defense against influenza, both for seasonal infections and pandemic outbreaks. Two main classes of drugs against influenza are in clinical use: M2-channel blockers and neuraminidase inhibitors. Nevertheless, because influenza strains that are resistant to these antivirals have been described, the search for novel compounds with different mechanisms of action is necessary. Here, we investigated the anti-influenza activity of a fungi-derived natural product, aureonitol. This compound inhibited influenza A and B virus replication. This compound was more effective against influenza A(H3N2), with an EC50 of 100 nM. Aureonitol cytoxicity was also very low, with a CC50 value of 1426 μM. Aureonitol inhibited influenza hemagglutination and, consequently, significantly impaired virus adsorption. Molecular modeling studies revealed that aureonitol docked in the sialic acid binding site of hemagglutinin, forming hydrogen bonds with highly conserved residues. Altogether, our results indicate that the chemical structure of aureonitol is promising for future anti-influenza drug design.
authors.affiliation: Laboratório de Vírus Respiratórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Carolina Q
authors.initials: CQ
authors.lastname: Sacramento
authors.affiliation: Laboratório de Vírus Respiratórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Andressa
authors.initials: A
authors.lastname: Marttorelli
authors.affiliation: Laboratório de Vírus Respiratórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Natalia
authors.initials: N
authors.lastname: Fintelman-Rodrigues
authors.affiliation: Laboratório de Vírus Respiratórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: de Freitas
authors.affiliation: Laboratório de Vírus Respiratórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, RJ, Brazil.
authors.forename: Gabrielle R
authors.initials: GR
authors.lastname: de Melo
authors.affiliation: Laboratório de Vírus Respiratórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Laboratório de Química de Produtos Naturais 5, Farmanguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Marco E N
authors.initials: ME
authors.lastname: Rocha
authors.affiliation: Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Kaiser
authors.affiliation: Laboratório de Taxonomia, Bioquímica e Bioprospecção de Fungos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Katia F
authors.initials: KF
authors.lastname: Rodrigues
authors.affiliation: Laboratório de Taxonomia, Bioquímica e Bioprospecção de Fungos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Gisela L
authors.initials: GL
authors.lastname: da Costa
authors.affiliation: Laboratório de Vírus Respiratórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Cristiane M
authors.initials: CM
authors.lastname: Alves
authors.affiliation: Laboratório de Vírus Respiratórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Santos-Filho
authors.affiliation: Laboratório de Taxonomia, Bioquímica e Bioprospecção de Fungos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Jussara P
authors.initials: JP
authors.lastname: Barbosa
authors.affiliation: Laboratório de Vírus Respiratórios, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Thiago Moreno L
authors.initials: TM
authors.lastname: Souza
mesh_terms: D000596:Amino Acids / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D003198:Computer Simulation; D017124:Conserved Sequence; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006384:Hemagglutination / Q000187:drug effects; D006388:Hemagglutinins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects*; D009981:Influenza B virus / Q000187:drug effects*; D061985:Madin Darby Canine Kidney Cells; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009439:Neuraminidase / Q000378:metabolism; D013997:Time Factors; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000596:Amino Acids; D000998:Antiviral Agents; D005663:Furans; D006388:Hemagglutinins; D008562:Membrane Glycoproteins; C533114:aureonitol; C018674:tetrahydrofuran; D009439:Neuraminidase