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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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Autores principales: Antanasijevic, Aleksandar, Cheng, Han, Wardrop, Duncan J., Rong, Lijun, Caffrey, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806803/
https://www.ncbi.nlm.nih.gov/pubmed/24194835
http://dx.doi.org/10.1371/journal.pone.0076363
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author Antanasijevic, Aleksandar
Cheng, Han
Wardrop, Duncan J.
Rong, Lijun
Caffrey, Michael
author_facet Antanasijevic, Aleksandar
Cheng, Han
Wardrop, Duncan J.
Rong, Lijun
Caffrey, Michael
author_sort Antanasijevic, Aleksandar
collection PubMed
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.
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spelling pubmed-38068032013-11-05 Inhibition of Influenza H7 Hemagglutinin-Mediated Entry Antanasijevic, Aleksandar Cheng, Han Wardrop, Duncan J. Rong, Lijun Caffrey, Michael PLoS One Research Article 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. Public Library of Science 2013-10-23 /pmc/articles/PMC3806803/ /pubmed/24194835 http://dx.doi.org/10.1371/journal.pone.0076363 Text en © 2013 Antanasijevic et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Antanasijevic, Aleksandar
Cheng, Han
Wardrop, Duncan J.
Rong, Lijun
Caffrey, Michael
Inhibition of Influenza H7 Hemagglutinin-Mediated Entry
title Inhibition of Influenza H7 Hemagglutinin-Mediated Entry
title_full Inhibition of Influenza H7 Hemagglutinin-Mediated Entry
title_fullStr Inhibition of Influenza H7 Hemagglutinin-Mediated Entry
title_full_unstemmed Inhibition of Influenza H7 Hemagglutinin-Mediated Entry
title_short Inhibition of Influenza H7 Hemagglutinin-Mediated Entry
title_sort inhibition of influenza h7 hemagglutinin-mediated entry
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806803/
https://www.ncbi.nlm.nih.gov/pubmed/24194835
http://dx.doi.org/10.1371/journal.pone.0076363
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