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

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Title Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase
Author Rudrawar, Santosh; Dyason, Jeffrey Clifford; Rameix-Welti, Marie-Anne; Rose, Faith Josephine; Kerry, Philip S.; Russell, Rupert J.M.; Werf, Sylvie van der; Thomson, Robin Joy; Naffakh, Nadia; von Itzstein, Mark
Journal Name Nature Communications
Year Published 2010
Place of publication United Kingdom
Publisher Nature Publishing Group
Abstract 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.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1038/ncomms1114
Volume 1
Page from 1
Page to 7
ISSN 2041-1723
Date Accessioned 2011-01-31
Language en_AU
Research Centre Institute for Glycomics
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Organic Chemical Synthesis; Structural Chemistry and Spectroscopy; Virology
URI http://hdl.handle.net/10072/37619
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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