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Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase

Influenza virus sialidase has an essential role in the virus' life cycle. Two distinct groups of influenza A virus sialidases have been established, that differ in the flexibility of the '150-loop', providing a more open active site in the apo form of the group-1 compared to group-2 e...

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Autores principales: Rudrawar, Santosh, Dyason, Jeffrey C., Rameix-Welti, Marie-Anne, Rose, Faith J., Kerry, Philip S., Russell, Rupert J. M., van der Werf, Sylvie, Thomson, Robin J., Naffakh, Nadia, von Itzstein, Mark
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060605/
https://www.ncbi.nlm.nih.gov/pubmed/21081911
http://dx.doi.org/10.1038/ncomms1114
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author Rudrawar, Santosh
Dyason, Jeffrey C.
Rameix-Welti, Marie-Anne
Rose, Faith J.
Kerry, Philip S.
Russell, Rupert J. M.
van der Werf, Sylvie
Thomson, Robin J.
Naffakh, Nadia
von Itzstein, Mark
author_facet Rudrawar, Santosh
Dyason, Jeffrey C.
Rameix-Welti, Marie-Anne
Rose, Faith J.
Kerry, Philip S.
Russell, Rupert J. M.
van der Werf, Sylvie
Thomson, Robin J.
Naffakh, Nadia
von Itzstein, Mark
author_sort Rudrawar, Santosh
collection PubMed
description Influenza virus sialidase has an essential role in the virus' life cycle. Two distinct groups of influenza A virus sialidases have been established, that differ in the flexibility of the '150-loop', providing a more open active site in the apo form of the group-1 compared to group-2 enzymes. In this study we show, through a multidisciplinary approach, that novel sialic acid-based derivatives can exploit this structural difference and selectively inhibit the activity of group-1 sialidases. We also demonstrate that group-1 sialidases from drug-resistant mutant influenza viruses are sensitive to these designed compounds. Moreover, we have determined, by protein X-ray crystallography, that these inhibitors lock open the group-1 sialidase flexible 150-loop, in agreement with our molecular modelling prediction. This is the first direct proof that compounds may be developed to selectively target the pandemic A/H1N1, avian A/H5N1 and other group-1 sialidase-containing viruses, based on an open 150-loop conformation of the enzyme.
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spelling pubmed-30606052011-03-29 Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase Rudrawar, Santosh Dyason, Jeffrey C. Rameix-Welti, Marie-Anne Rose, Faith J. Kerry, Philip S. Russell, Rupert J. M. van der Werf, Sylvie Thomson, Robin J. Naffakh, Nadia von Itzstein, Mark Nat Commun Article Influenza virus sialidase has an essential role in the virus' life cycle. Two distinct groups of influenza A virus sialidases have been established, that differ in the flexibility of the '150-loop', providing a more open active site in the apo form of the group-1 compared to group-2 enzymes. In this study we show, through a multidisciplinary approach, that novel sialic acid-based derivatives can exploit this structural difference and selectively inhibit the activity of group-1 sialidases. We also demonstrate that group-1 sialidases from drug-resistant mutant influenza viruses are sensitive to these designed compounds. Moreover, we have determined, by protein X-ray crystallography, that these inhibitors lock open the group-1 sialidase flexible 150-loop, in agreement with our molecular modelling prediction. This is the first direct proof that compounds may be developed to selectively target the pandemic A/H1N1, avian A/H5N1 and other group-1 sialidase-containing viruses, based on an open 150-loop conformation of the enzyme. Nature Publishing Group 2010-11-16 /pmc/articles/PMC3060605/ /pubmed/21081911 http://dx.doi.org/10.1038/ncomms1114 Text en Copyright © 2010, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Article
Rudrawar, Santosh
Dyason, Jeffrey C.
Rameix-Welti, Marie-Anne
Rose, Faith J.
Kerry, Philip S.
Russell, Rupert J. M.
van der Werf, Sylvie
Thomson, Robin J.
Naffakh, Nadia
von Itzstein, Mark
Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
title Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
title_full Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
title_fullStr Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
title_full_unstemmed Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
title_short Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
title_sort novel sialic acid derivatives lock open the 150-loop of an influenza a virus group-1 sialidase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060605/
https://www.ncbi.nlm.nih.gov/pubmed/21081911
http://dx.doi.org/10.1038/ncomms1114
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