Inhibition of influenza H7 hemagglutinin-mediated entry
The recent outbreak of H7N9 influenza in China is of high concern to public health. H7 hemagglutinin (HA) plays a critical role in influenza entry and thus HA presents an attractive target for antivirals. Previous studies have suggested that the small molecule tert-butyl hydroquinone (TBHQ) inhibits...
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| description | The recent outbreak of H7N9 influenza in China is of high concern to public health. H7 hemagglutinin (HA) plays a critical role in influenza entry and thus HA presents an attractive target for antivirals. Previous studies have suggested that the small molecule tert-butyl hydroquinone (TBHQ) inhibits the entry of influenza H3 HA by binding to the stem loop of HA and stabilizing the neutral pH conformation of HA, thereby disrupting the membrane fusion step. Based on amino acid sequence, structure and immunogenicity, H7 is a related Group 2 HA. In this work we show, using a pseudovirus entry assay, that TBHQ inhibits H7 HA-mediated entry, as well as H3 HA-mediated entry, with an IC50 ~ 6 µM. Using NMR, we show that TBHQ binds to the H7 stem loop region. STD NMR experiments indicate that the aromatic ring of TBHQ makes extensive contact with the H7 HA surface. Limited proteolysis experiments indicate that TBHQ inhibits influenza entry by stabilizing the H7 HA neutral pH conformation. Together, this work suggests that the stem loop region of H7 HA is an attractive target for therapeutic intervention and that TBHQ, which is a widely used food preservative, is a promising lead compound. |
| doi_str_mv | 10.1371/journal.pone.0076363 |
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H7 hemagglutinin (HA) plays a critical role in influenza entry and thus HA presents an attractive target for antivirals. Previous studies have suggested that the small molecule tert-butyl hydroquinone (TBHQ) inhibits the entry of influenza H3 HA by binding to the stem loop of HA and stabilizing the neutral pH conformation of HA, thereby disrupting the membrane fusion step. Based on amino acid sequence, structure and immunogenicity, H7 is a related Group 2 HA. In this work we show, using a pseudovirus entry assay, that TBHQ inhibits H7 HA-mediated entry, as well as H3 HA-mediated entry, with an IC50 ~ 6 µM. Using NMR, we show that TBHQ binds to the H7 stem loop region. STD NMR experiments indicate that the aromatic ring of TBHQ makes extensive contact with the H7 HA surface. Limited proteolysis experiments indicate that TBHQ inhibits influenza entry by stabilizing the H7 HA neutral pH conformation. Together, this work suggests that the stem loop region of H7 HA is an attractive target for therapeutic intervention and that TBHQ, which is a widely used food preservative, is a promising lead compound.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0076363</identifier><identifier>PMID: 24194835</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Sequence ; Antiviral agents ; Base Sequence ; Biochemistry ; Cell culture ; China - epidemiology ; Conformation ; Disease Outbreaks - prevention & control ; Fatalities ; Food preservatives ; Health aspects ; Hemagglutinin Glycoproteins, Influenza Virus - genetics ; Hemagglutinin Glycoproteins, Influenza Virus - metabolism ; Hemagglutinins ; Humans ; Hydroquinone ; Hydroquinones - pharmacology ; Immunogenicity ; Immunology ; Influenza ; Influenza A Virus, H7N9 Subtype ; Influenza, Human - epidemiology ; Influenza, Human - prevention & control ; Inhibitory Concentration 50 ; Lectins ; Ligands ; Membrane fusion ; Molecular Sequence Data ; Monoclonal antibodies ; NMR ; Nuclear magnetic resonance ; Nuclear Magnetic Resonance, Biomolecular ; Outbreaks ; Penicillin ; pH effects ; Proteins ; Proteolysis ; Public health ; Sequence Analysis, DNA ; Swine flu ; t-Butylhydroquinone ; Virus Internalization - drug effects ; Viruses</subject><ispartof>PloS one, 2013-10, Vol.8 (10), p.e76363</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Antanasijevic et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Antanasijevic et al 2013 Antanasijevic et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-c2eaf6beb126ce95b1718b454a00febf5cf2aebca8daddb8ae39733c0e0b06b83</citedby><cites>FETCH-LOGICAL-c692t-c2eaf6beb126ce95b1718b454a00febf5cf2aebca8daddb8ae39733c0e0b06b83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806803/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806803/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24194835$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Zhang, Luwen</contributor><creatorcontrib>Antanasijevic, Aleksandar</creatorcontrib><creatorcontrib>Cheng, Han</creatorcontrib><creatorcontrib>Wardrop, Duncan J</creatorcontrib><creatorcontrib>Rong, Lijun</creatorcontrib><creatorcontrib>Caffrey, Michael</creatorcontrib><title>Inhibition of influenza H7 hemagglutinin-mediated entry</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The recent outbreak of H7N9 influenza in China is of high concern to public health. H7 hemagglutinin (HA) plays a critical role in influenza entry and thus HA presents an attractive target for antivirals. Previous studies have suggested that the small molecule tert-butyl hydroquinone (TBHQ) inhibits the entry of influenza H3 HA by binding to the stem loop of HA and stabilizing the neutral pH conformation of HA, thereby disrupting the membrane fusion step. Based on amino acid sequence, structure and immunogenicity, H7 is a related Group 2 HA. In this work we show, using a pseudovirus entry assay, that TBHQ inhibits H7 HA-mediated entry, as well as H3 HA-mediated entry, with an IC50 ~ 6 µM. Using NMR, we show that TBHQ binds to the H7 stem loop region. STD NMR experiments indicate that the aromatic ring of TBHQ makes extensive contact with the H7 HA surface. Limited proteolysis experiments indicate that TBHQ inhibits influenza entry by stabilizing the H7 HA neutral pH conformation. Together, this work suggests that the stem loop region of H7 HA is an attractive target for therapeutic intervention and that TBHQ, which is a widely used food preservative, is a promising lead compound.</description><subject>Amino Acid Sequence</subject><subject>Antiviral agents</subject><subject>Base Sequence</subject><subject>Biochemistry</subject><subject>Cell culture</subject><subject>China - epidemiology</subject><subject>Conformation</subject><subject>Disease Outbreaks - prevention & control</subject><subject>Fatalities</subject><subject>Food preservatives</subject><subject>Health aspects</subject><subject>Hemagglutinin Glycoproteins, Influenza Virus - genetics</subject><subject>Hemagglutinin Glycoproteins, Influenza Virus - metabolism</subject><subject>Hemagglutinins</subject><subject>Humans</subject><subject>Hydroquinone</subject><subject>Hydroquinones - pharmacology</subject><subject>Immunogenicity</subject><subject>Immunology</subject><subject>Influenza</subject><subject>Influenza A Virus, H7N9 Subtype</subject><subject>Influenza, Human - epidemiology</subject><subject>Influenza, Human - prevention & control</subject><subject>Inhibitory Concentration 50</subject><subject>Lectins</subject><subject>Ligands</subject><subject>Membrane fusion</subject><subject>Molecular Sequence Data</subject><subject>Monoclonal antibodies</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Nuclear Magnetic Resonance, Biomolecular</subject><subject>Outbreaks</subject><subject>Penicillin</subject><subject>pH effects</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Public health</subject><subject>Sequence Analysis, DNA</subject><subject>Swine flu</subject><subject>t-Butylhydroquinone</subject><subject>Virus Internalization - drug effects</subject><subject>Viruses</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl9rFDEUxQdRbF39BqILgujDrskkk0lehFLULhQK_nsNN5k7s1lmk-1kRqyf3mx3WnakD5KHhOR3z81JTpa9pGRJWUk_bMLQeWiXu-BxSUgpmGCPslOqWL4QOWGPj9Yn2bMYN4QUTArxNDvJOVVcsuI0K1d-7YzrXfDzUM-dr9sB_R-YX5TzNW6hadqhd975xRYrBz1Wc_R9d_M8e1JDG_HFOM-yH58_fT-_WFxefVmdn10urFB5v7A5Qi0MGpoLi6owtKTS8IIDITWaurB1DmgsyAqqykhApkrGLEFiiDCSzbLXB91dG6IePUdNOS-kFCo5mmWrA1EF2Ohd57bQ3egATt9uhK7R0PXOtqgLwXJGBNpScc4lBU4MlaQAqupKWUxaH8dug0l-7d4qtBPR6Yl3a92EX5pJIiRhSeDdKNCF6wFjr7cuWmxb8BiG23urXMjUO6Fv_kEfdjdSDSQD6XtC6mv3ovqMl0kmV4okavkAlUaFW2dTQGqX9icF7ycFienxd9_AEKNeffv6_-zVzyn79ohdI7T9OoZ9hIKPU5AfQNuFGDus7x-ZEr3P991r6H2-9ZjvVPbq-IPui-4Czf4CfZP1Cg</recordid><startdate>20131023</startdate><enddate>20131023</enddate><creator>Antanasijevic, Aleksandar</creator><creator>Cheng, Han</creator><creator>Wardrop, Duncan J</creator><creator>Rong, Lijun</creator><creator>Caffrey, Michael</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>COVID</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131023</creationdate><title>Inhibition of influenza H7 hemagglutinin-mediated entry</title><author>Antanasijevic, Aleksandar ; Cheng, Han ; Wardrop, Duncan J ; Rong, Lijun ; Caffrey, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-c2eaf6beb126ce95b1718b454a00febf5cf2aebca8daddb8ae39733c0e0b06b83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino Acid Sequence</topic><topic>Antiviral agents</topic><topic>Base Sequence</topic><topic>Biochemistry</topic><topic>Cell culture</topic><topic>China - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Antanasijevic, Aleksandar</au><au>Cheng, Han</au><au>Wardrop, Duncan J</au><au>Rong, Lijun</au><au>Caffrey, Michael</au><au>Zhang, Luwen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of influenza H7 hemagglutinin-mediated entry</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-10-23</date><risdate>2013</risdate><volume>8</volume><issue>10</issue><spage>e76363</spage><pages>e76363-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The recent outbreak of H7N9 influenza in China is of high concern to public health. H7 hemagglutinin (HA) plays a critical role in influenza entry and thus HA presents an attractive target for antivirals. Previous studies have suggested that the small molecule tert-butyl hydroquinone (TBHQ) inhibits the entry of influenza H3 HA by binding to the stem loop of HA and stabilizing the neutral pH conformation of HA, thereby disrupting the membrane fusion step. Based on amino acid sequence, structure and immunogenicity, H7 is a related Group 2 HA. In this work we show, using a pseudovirus entry assay, that TBHQ inhibits H7 HA-mediated entry, as well as H3 HA-mediated entry, with an IC50 ~ 6 µM. Using NMR, we show that TBHQ binds to the H7 stem loop region. STD NMR experiments indicate that the aromatic ring of TBHQ makes extensive contact with the H7 HA surface. Limited proteolysis experiments indicate that TBHQ inhibits influenza entry by stabilizing the H7 HA neutral pH conformation. Together, this work suggests that the stem loop region of H7 HA is an attractive target for therapeutic intervention and that TBHQ, which is a widely used food preservative, is a promising lead compound.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24194835</pmid><doi>10.1371/journal.pone.0076363</doi><tpages>e76363</tpages><oa>free_for_read</oa></addata></record> |
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| source | Electronic Journals Library; Open Access: PubMed Central; MEDLINE; Public Library of Science; DOAJ Directory of Open Access Journals; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence Antiviral agents Base Sequence Biochemistry Cell culture China - epidemiology Conformation Disease Outbreaks - prevention & control Fatalities Food preservatives Health aspects Hemagglutinin Glycoproteins, Influenza Virus - genetics Hemagglutinin Glycoproteins, Influenza Virus - metabolism Hemagglutinins Humans Hydroquinone Hydroquinones - pharmacology Immunogenicity Immunology Influenza Influenza A Virus, H7N9 Subtype Influenza, Human - epidemiology Influenza, Human - prevention & control Inhibitory Concentration 50 Lectins Ligands Membrane fusion Molecular Sequence Data Monoclonal antibodies NMR Nuclear magnetic resonance Nuclear Magnetic Resonance, Biomolecular Outbreaks Penicillin pH effects Proteins Proteolysis Public health Sequence Analysis, DNA Swine flu t-Butylhydroquinone Virus Internalization - drug effects Viruses |
| title | Inhibition of influenza H7 hemagglutinin-mediated entry |
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