Inhibition of Influenza Virus Hemagglutinin-Mediated Membrane Fusion by a Compound Related to Podocarpic Acid
Identifieur interne : 001B02 ( Main/Exploration ); précédent : 001B01; suivant : 001B03Inhibition of Influenza Virus Hemagglutinin-Mediated Membrane Fusion by a Compound Related to Podocarpic Acid
Auteurs : K. A. Staschke [États-Unis] ; S. D. Hatch [États-Unis] ; J. C. Tang [États-Unis] ; W. J. Hornback [États-Unis] ; J. E. Munroe [États-Unis] ; J. M. Colacino [États-Unis] ; M. A. Muesing [États-Unis]Source :
- Virology [ 0042-6822 ] ; 1998.
English descriptors
- Teeft :
- Acid sequence, Amantadine, Amino, Amino acid changes, Amino acid substitutions, Amino acids, Assay, Cdna, Cell biol, Cell monolayers, Conformation, Conformational, Conformational change, Conformational switch, Electron microscopy, Endosomal, Erythrocyte, Fusion, Fusion peptide, Fusogenic, Fusogenic function, Fusogenic state, Gene segment, Genetic analysis, Genetic characterization, Hemagglutinin, High concentrations, Human erythrocytes, Infectivity, Influenza, Influenza hemagglutinin, Influenza virus, Influenza virus hemagglutinin, Influenza virus replication, Influenza virus variants, Influenza viruses, Inhibitor, Mdck, Mdck cells, Membrane, Membrane fusion, Metastable, Metastable conformation, Monolayers, Mutant, Mutation, Neuraminidase inhibitor, Norakin, Norakinr influenza viruses, Peptide, Plaque, Plaque assay, Podocarpic, Podocarpic acid, Replication, Resistant viruses, Room temperature, Sequence analysis, Skehel, Variant, Viral, Viral protein synthesis, Virol, Virus, Virus replication.
Abstract
Abstract: Entry of influenza virus into the host cell is dependent on the fusion of the viral envelope with the endosomal membrane and is mediated by a low-pH-induced change of the viral hemagglutinin (HA) to a conformation that is fusogenic. A compound related to podocarpic acid (180299) was identified that inhibits multicycle replication of influenza A/Kawasaki/86 (H1N1) virus in culture. Treatment of Madin–Darby canine kidney (MDCK) cells with 180299 at 1 h before infection resulted in the inhibition of viral protein synthesis. Addition of 20 μg of 180299/ml at 1 h p.i. had no effect, indicating that 180299 affects an early step of the influenza viral replication cycle. Genetic analysis of reassortants between sensitive and resistant viruses demonstrated that hemagglutinin (HA) conferred the 180299-resistant (180299r) phenotype. Twelve independent isolates of influenza A/Kawasaki/86 were selected for resistance to 180299, and sequence analysis revealed that each of these viruses contained amino acid substitutions in the HA. These mutations are dispersed throughout the HA primary amino acid sequence and cluster in one of two regions: the interface between HA1and HA2and in a region near the fusion domain of HA2. When compared with the parent virus, the pH-of-inactivation of the resistant mutants was increased by 0.3 to 0.6 pH unit, suggesting that the mutant HAs undergo the conformational change at an elevated pH. Fusion of human erythrocytes to MDCK cells infected with parent influenza A/Kawasaki/86 was inhibited by 180299 (0.1–10 μg/ml) in a concentration-dependent manner, whereas fusion of erythrocytes to MDCK cells infected with 180299rmutants was not affected. These results suggest that 180299 interacts with the neutral pH conformation of influenza A HA and prevents the low-pH-induced change of HA to its fusogenic conformation.
Url:
DOI: 10.1006/viro.1998.9273
Affiliations:
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Tang</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Lilly Research Laboratories, Indianapolis</wicri:cityArea></affiliation></author><author><name sortKey="Hornback, W J" sort="Hornback, W J" uniqKey="Hornback W" first="W. J." last="Hornback">W. J. Hornback</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Lilly Research Laboratories, Indianapolis</wicri:cityArea></affiliation></author><author><name sortKey="Munroe, J E" sort="Munroe, J E" uniqKey="Munroe J" first="J. E." last="Munroe">J. E. 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Muesing</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Lilly Research Laboratories, Indianapolis</wicri:cityArea></affiliation></author></analytic><monogr></monogr><series><title level="j">Virology</title><title level="j" type="abbrev">YVIRO</title><idno type="ISSN">0042-6822</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998">1998</date><biblScope unit="volume">248</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="264">264</biblScope><biblScope unit="page" to="274">274</biblScope></imprint><idno type="ISSN">0042-6822</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0042-6822</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Acid sequence</term><term>Amantadine</term><term>Amino</term><term>Amino acid changes</term><term>Amino acid substitutions</term><term>Amino acids</term><term>Assay</term><term>Cdna</term><term>Cell biol</term><term>Cell monolayers</term><term>Conformation</term><term>Conformational</term><term>Conformational change</term><term>Conformational switch</term><term>Electron microscopy</term><term>Endosomal</term><term>Erythrocyte</term><term>Fusion</term><term>Fusion peptide</term><term>Fusogenic</term><term>Fusogenic function</term><term>Fusogenic state</term><term>Gene segment</term><term>Genetic analysis</term><term>Genetic characterization</term><term>Hemagglutinin</term><term>High concentrations</term><term>Human erythrocytes</term><term>Infectivity</term><term>Influenza</term><term>Influenza hemagglutinin</term><term>Influenza virus</term><term>Influenza virus hemagglutinin</term><term>Influenza virus replication</term><term>Influenza virus variants</term><term>Influenza viruses</term><term>Inhibitor</term><term>Mdck</term><term>Mdck cells</term><term>Membrane</term><term>Membrane fusion</term><term>Metastable</term><term>Metastable conformation</term><term>Monolayers</term><term>Mutant</term><term>Mutation</term><term>Neuraminidase inhibitor</term><term>Norakin</term><term>Norakinr influenza viruses</term><term>Peptide</term><term>Plaque</term><term>Plaque assay</term><term>Podocarpic</term><term>Podocarpic acid</term><term>Replication</term><term>Resistant viruses</term><term>Room temperature</term><term>Sequence analysis</term><term>Skehel</term><term>Variant</term><term>Viral</term><term>Viral protein synthesis</term><term>Virol</term><term>Virus</term><term>Virus replication</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Entry of influenza virus into the host cell is dependent on the fusion of the viral envelope with the endosomal membrane and is mediated by a low-pH-induced change of the viral hemagglutinin (HA) to a conformation that is fusogenic. A compound related to podocarpic acid (180299) was identified that inhibits multicycle replication of influenza A/Kawasaki/86 (H1N1) virus in culture. Treatment of Madin–Darby canine kidney (MDCK) cells with 180299 at 1 h before infection resulted in the inhibition of viral protein synthesis. Addition of 20 μg of 180299/ml at 1 h p.i. had no effect, indicating that 180299 affects an early step of the influenza viral replication cycle. Genetic analysis of reassortants between sensitive and resistant viruses demonstrated that hemagglutinin (HA) conferred the 180299-resistant (180299r) phenotype. Twelve independent isolates of influenza A/Kawasaki/86 were selected for resistance to 180299, and sequence analysis revealed that each of these viruses contained amino acid substitutions in the HA. These mutations are dispersed throughout the HA primary amino acid sequence and cluster in one of two regions: the interface between HA1and HA2and in a region near the fusion domain of HA2. When compared with the parent virus, the pH-of-inactivation of the resistant mutants was increased by 0.3 to 0.6 pH unit, suggesting that the mutant HAs undergo the conformational change at an elevated pH. Fusion of human erythrocytes to MDCK cells infected with parent influenza A/Kawasaki/86 was inhibited by 180299 (0.1–10 μg/ml) in a concentration-dependent manner, whereas fusion of erythrocytes to MDCK cells infected with 180299rmutants was not affected. These results suggest that 180299 interacts with the neutral pH conformation of influenza A HA and prevents the low-pH-induced change of HA to its fusogenic conformation.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Indiana</li></region></list><tree><country name="États-Unis"><region name="Indiana"><name sortKey="Staschke, K A" sort="Staschke, K A" uniqKey="Staschke K" first="K. A." last="Staschke">K. A. Staschke</name></region><name sortKey="Colacino, J M" sort="Colacino, J M" uniqKey="Colacino J" first="J. M." last="Colacino">J. M. Colacino</name><name sortKey="Hatch, S D" sort="Hatch, S D" uniqKey="Hatch S" first="S. D." last="Hatch">S. D. Hatch</name><name sortKey="Hornback, W J" sort="Hornback, W J" uniqKey="Hornback W" first="W. J." last="Hornback">W. J. Hornback</name><name sortKey="Muesing, M A" sort="Muesing, M A" uniqKey="Muesing M" first="M. A." last="Muesing">M. A. Muesing</name><name sortKey="Munroe, J E" sort="Munroe, J E" uniqKey="Munroe J" first="J. E." last="Munroe">J. E. Munroe</name><name sortKey="Tang, J C" sort="Tang, J C" uniqKey="Tang J" first="J. C." last="Tang">J. C. Tang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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